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Everolimus in Patients With Pancreatic Neuroendocrine Tumors Metastatic to the Liver Previously Treated With Surgery

Primary Purpose

Gastrinoma, Glucagonoma, Insulinoma

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
everolimus
placebo
Sponsored by
ECOG-ACRIN Cancer Research Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Gastrinoma focused on measuring everolimus, randomized, metastatic pancreatic neuroendocrine tumors, liver

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA:

  • Patients must have histologically or pathologically confirmed metastatic low or intermediate grade pancreatic neuroendocrine tumor(s) to the liver as per the Klimstra guidelines
  • Patients must have recovered from an R0 or R1 resection of all disease (including resection of a primary primitive neuroectodermal tumor [PNET] if present); patients may have had resection plus microwave or radiofrequency ablation, provided that no ablated lesion was >= 5 cm prior to ablation
  • Patients must be within 4 to 8 weeks from the completion of surgery at time of randomization
  • Patients must have paraffin-embedded fixed metastatic tumor tissue available for submission for central review; core biopsy or surgical specimens required
  • Patients must have post-operative computed tomography (CT) or magnetic resonance imaging (MRI) prior to randomization and =< 4 weeks after completion of surgery to confirm disease status; patients must be able to tolerate CT or MRI imaging including contrast agents as required for the protocol
  • Women of child-bearing potential and sexually active males must be strongly advised to use an accepted and highly effective method of contraception or abstain from sexual intercourse for the duration of their treatment through 8 weeks after their last dose of protocol therapy; women of child-bearing potential, sexually active males, and the female partners of male participants should be advised of the risk of becoming pregnant or fathering a child while receiving protocol treatment; should a woman become pregnant while participating in this study, she should inform her treating physician immediately; if a man impregnates a woman while participating in this study, he should inform his treating physician immediately
  • Prior treatment with sunitinib and/or cytotoxic chemotherapy are allowed provided last dose was > 30 days prior to randomization
  • Prior chemoembolization is allowed provided last dose was > 30 days prior to randomization
  • Total bilirubin =< 1.5 X institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 X institutional ULN
  • Serum creatinine =< 1.5 X institutional ULN or creatinine clearance >= 60 mL/min for patients with creatinine levels above 1.5 X institutional normal
  • Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =< 2.5 x ULN
  • Absolute neutrophil count >= 1,500/mm^3
  • Leukocytes >= 3,000/mm^3
  • Platelets >= 100,000/mm^3
  • Hemoglobin >= 9 g/dL
  • Patients with a history of the following within =< 12 months of randomization are not eligible

    • Arterial thromboembolic events
    • Unstable angina
    • Myocardial infarction
  • Patients with known history of abnormal pulmonary function must have documentation of diffusing capacity of the lung for carbon monoxide (DLCO) of > 50% predicted and oxygen saturation (SaO2) of > 87% at rest on room air =< 4 weeks prior to randomization
  • Patients with unexplained pulmonary infiltrates must have pulmonary function tests within the institutional limits of normal =< 4 weeks prior to randomization
  • Patients with poorly controlled diabetes mellitus as defined by hemoglobin A1c (HbA1c) > 8% despite adequate therapy are ineligible; patients with a known history of impaired fasting glucose or diabetes mellitus must have blood glucose and antidiabetic treatment monitored closely throughout the trial and adjusted as necessary
  • Patients may not be receiving any other investigational agents while on study treatment; prior treatment with other investigational agent is allowed provided last dose was >= 30 days prior to randomization
  • Patients must NOT have received live attenuated vaccines =< 1 week prior to randomization; patients should also be advised not to receive live attenuated vaccines during the study and to avoid close contact with others who have received live attenuated vaccines; examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines
  • Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Patients must have life expectancy >= 12 weeks
  • Patients should be advised to avoid drugs or foods that are known potent cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors or inducers

EXCLUSION CRITERIA:

  • Patients have received prior everolimus
  • Patients have either clinically apparent central nervous system metastases or carcinomatous meningitis =< 6 months prior to randomization
  • Women are pregnant or breast-feeding; all females of childbearing potential must have a blood test within 2 weeks prior to randomization to rule out pregnancy
  • Patients are on chronic treatment with corticosteroids or other immunosuppressive agents; topical or inhaled corticosteroids are allowed
  • Patients have history of allergic reactions attributed to compounds of similar chemical or biologic composition to everolimus
  • Patients have known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus)
  • Patients have absorption issues that would limit the ability to absorb everolimus
  • Patients have a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study
  • Patients have previous or concurrent malignancy; exceptions are made for patients who meet any of the following conditions:

    • Non-melanoma skin cancer, in situ cervical cancer, breast cancer in situ, or superficial bladder cancer (noninvasive papillary carcinoma or carcinoma in situ); OR
    • Prior malignancy completely excised or removed and patient has been continuously disease free for > 5 years
  • Patients have severe and/or uncontrolled medical conditions such as:

    • Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =< 6 months prior to randomization, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease
    • Symptomatic congestive heart failure of New York Heart Association class III or IV
    • Active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable hepatitis B virus [HBV]-deoxyribonucleic acid [DNA] and/or positive hepatitis B surface antigen [HbsAg], quantifiable hepatitis C virus [HCV]-ribonucleic acid [RNA])
    • Active, bleeding diathesis
  • Patients have known history of human immunodeficiency virus (HIV) seropositivity
  • Patients have experienced thrombotic events (deep vein thrombosis, pulmonary embolism) =< 3 months prior to randomization
  • Patients have liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis at randomization; patients at increased risk for hepatitis B or hepatitis C must be screened for hepatitis prior to randomization
  • Patients have ongoing cardiac dysrhythmia of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (v4.0) grade >= 2, uncontrolled atrial fibrillation of any grade, or corrected QT (QTc) interval > 470 msec
  • Patients have history of severely impaired pulmonary function for their age

Sites / Locations

  • Ecog-Acrin

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm A (everolimus)

Arm B (placebo)

Arm Description

Patients receive everolimus PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Patients receive placebo PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Disease Free Survival (DFS)
DFS is defined as time from randomization to disease recurrence or death, whichever occurred first. Patients who are still alive are censored at the last date of known free of recurrence.

Secondary Outcome Measures

Overall Survival (OS)
OS is defined as time from randomization to death from any cause. Patients who are still alive are censored at the last date of known alive.

Full Information

First Posted
January 7, 2014
Last Updated
June 14, 2023
Sponsor
ECOG-ACRIN Cancer Research Group
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT02031536
Brief Title
Everolimus in Patients With Pancreatic Neuroendocrine Tumors Metastatic to the Liver Previously Treated With Surgery
Official Title
A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine Tumors to the Liver
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Terminated
Why Stopped
Slow accrual
Study Start Date
April 10, 2014 (Actual)
Primary Completion Date
July 19, 2017 (Actual)
Study Completion Date
July 19, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ECOG-ACRIN Cancer Research Group
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This randomized phase II trial studies how well everolimus works in treating patients with pancreatic neuroendocrine tumors metastatic to the liver previously treated with surgery. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving everolimus after surgery may kill any tumors cells that remain.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate if the addition of adjuvant everolimus to the R0 or R1 surgical resection of pancreatic neuroendocrine tumor metastases to the liver will result in an improvement in disease free survival. SECONDARY OBJECTIVES: I. To evaluate if the addition of adjuvant everolimus to the R0 or R1 surgical resection of pancreatic neuroendocrine tumor metastases to the liver will result in an improvement in overall survival. II. To evaluate the toxicity associated with adjuvant everolimus following resection in patients with metastatic pancreatic neuroendocrine tumors to the liver. OUTLINE: Patients are randomized to 1 of 2 treatment arms in a 1:1 ratio. ARM A: Patients receive everolimus orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive placebo PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years. PROJECTED ACCRUAL: 150 patients

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Gastrinoma, Glucagonoma, Insulinoma, Liver Metastases, Pancreatic Polypeptide Tumor, Recurrent Islet Cell Carcinoma, Somatostatinoma
Keywords
everolimus, randomized, metastatic pancreatic neuroendocrine tumors, liver

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm A (everolimus)
Arm Type
Experimental
Arm Description
Patients receive everolimus PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Arm Title
Arm B (placebo)
Arm Type
Placebo Comparator
Arm Description
Patients receive placebo PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
everolimus
Other Intervention Name(s)
42-O-(2-hydroxy)ethyl rapamycin, Afinitor, RAD001
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
placebo
Other Intervention Name(s)
PLCB
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Disease Free Survival (DFS)
Description
DFS is defined as time from randomization to disease recurrence or death, whichever occurred first. Patients who are still alive are censored at the last date of known free of recurrence.
Time Frame
assessed every 12 weeks while on treatment and then every 3 months if < 2 years from study entry; every 6 months up to 5 years from study entry or recurrence, whichever occurred first
Secondary Outcome Measure Information:
Title
Overall Survival (OS)
Description
OS is defined as time from randomization to death from any cause. Patients who are still alive are censored at the last date of known alive.
Time Frame
assessed every 3 months if < 2 years from study entry, and every 6 months up to 5 years from study entry or death, whichever occurred first

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA: Patients must have histologically or pathologically confirmed metastatic low or intermediate grade pancreatic neuroendocrine tumor(s) to the liver as per the Klimstra guidelines Patients must have recovered from an R0 or R1 resection of all disease (including resection of a primary primitive neuroectodermal tumor [PNET] if present); patients may have had resection plus microwave or radiofrequency ablation, provided that no ablated lesion was >= 5 cm prior to ablation Patients must be within 4 to 8 weeks from the completion of surgery at time of randomization Patients must have paraffin-embedded fixed metastatic tumor tissue available for submission for central review; core biopsy or surgical specimens required Patients must have post-operative computed tomography (CT) or magnetic resonance imaging (MRI) prior to randomization and =< 4 weeks after completion of surgery to confirm disease status; patients must be able to tolerate CT or MRI imaging including contrast agents as required for the protocol Women of child-bearing potential and sexually active males must be strongly advised to use an accepted and highly effective method of contraception or abstain from sexual intercourse for the duration of their treatment through 8 weeks after their last dose of protocol therapy; women of child-bearing potential, sexually active males, and the female partners of male participants should be advised of the risk of becoming pregnant or fathering a child while receiving protocol treatment; should a woman become pregnant while participating in this study, she should inform her treating physician immediately; if a man impregnates a woman while participating in this study, he should inform his treating physician immediately Prior treatment with sunitinib and/or cytotoxic chemotherapy are allowed provided last dose was > 30 days prior to randomization Prior chemoembolization is allowed provided last dose was > 30 days prior to randomization Total bilirubin =< 1.5 X institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 X institutional ULN Serum creatinine =< 1.5 X institutional ULN or creatinine clearance >= 60 mL/min for patients with creatinine levels above 1.5 X institutional normal Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =< 2.5 x ULN Absolute neutrophil count >= 1,500/mm^3 Leukocytes >= 3,000/mm^3 Platelets >= 100,000/mm^3 Hemoglobin >= 9 g/dL Patients with a history of the following within =< 12 months of randomization are not eligible Arterial thromboembolic events Unstable angina Myocardial infarction Patients with known history of abnormal pulmonary function must have documentation of diffusing capacity of the lung for carbon monoxide (DLCO) of > 50% predicted and oxygen saturation (SaO2) of > 87% at rest on room air =< 4 weeks prior to randomization Patients with unexplained pulmonary infiltrates must have pulmonary function tests within the institutional limits of normal =< 4 weeks prior to randomization Patients with poorly controlled diabetes mellitus as defined by hemoglobin A1c (HbA1c) > 8% despite adequate therapy are ineligible; patients with a known history of impaired fasting glucose or diabetes mellitus must have blood glucose and antidiabetic treatment monitored closely throughout the trial and adjusted as necessary Patients may not be receiving any other investigational agents while on study treatment; prior treatment with other investigational agent is allowed provided last dose was >= 30 days prior to randomization Patients must NOT have received live attenuated vaccines =< 1 week prior to randomization; patients should also be advised not to receive live attenuated vaccines during the study and to avoid close contact with others who have received live attenuated vaccines; examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 1 Patients must have life expectancy >= 12 weeks Patients should be advised to avoid drugs or foods that are known potent cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors or inducers EXCLUSION CRITERIA: Patients have received prior everolimus Patients have either clinically apparent central nervous system metastases or carcinomatous meningitis =< 6 months prior to randomization Women are pregnant or breast-feeding; all females of childbearing potential must have a blood test within 2 weeks prior to randomization to rule out pregnancy Patients are on chronic treatment with corticosteroids or other immunosuppressive agents; topical or inhaled corticosteroids are allowed Patients have history of allergic reactions attributed to compounds of similar chemical or biologic composition to everolimus Patients have known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus) Patients have absorption issues that would limit the ability to absorb everolimus Patients have a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study Patients have previous or concurrent malignancy; exceptions are made for patients who meet any of the following conditions: Non-melanoma skin cancer, in situ cervical cancer, breast cancer in situ, or superficial bladder cancer (noninvasive papillary carcinoma or carcinoma in situ); OR Prior malignancy completely excised or removed and patient has been continuously disease free for > 5 years Patients have severe and/or uncontrolled medical conditions such as: Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =< 6 months prior to randomization, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease Symptomatic congestive heart failure of New York Heart Association class III or IV Active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable hepatitis B virus [HBV]-deoxyribonucleic acid [DNA] and/or positive hepatitis B surface antigen [HbsAg], quantifiable hepatitis C virus [HCV]-ribonucleic acid [RNA]) Active, bleeding diathesis Patients have known history of human immunodeficiency virus (HIV) seropositivity Patients have experienced thrombotic events (deep vein thrombosis, pulmonary embolism) =< 3 months prior to randomization Patients have liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis at randomization; patients at increased risk for hepatitis B or hepatitis C must be screened for hepatitis prior to randomization Patients have ongoing cardiac dysrhythmia of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (v4.0) grade >= 2, uncontrolled atrial fibrillation of any grade, or corrected QT (QTc) interval > 470 msec Patients have history of severely impaired pulmonary function for their age
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Steven Libutti
Organizational Affiliation
Eastern Cooperative Oncology Group
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ecog-Acrin
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Everolimus in Patients With Pancreatic Neuroendocrine Tumors Metastatic to the Liver Previously Treated With Surgery

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