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

A Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Adjuvant Everolimus Following the Resection of Metastatic Pancreatic Neuroendocrine Tumors to the Liver

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.

Study Overview

• Status: Terminated
• Conditions: Liver Metastases; Gastrinoma; Glucagonoma; Insulinoma; Pancreatic Polypeptide Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma
• Intervention / Treatment: Drug: everolimus; Other: placebo

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

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Ecog-Acrin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A (everolimus); 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.	Drug: everolimus; Given PO; Other Names: Afinitor; RAD001; 42-O-(2-hydroxy)ethyl rapamycin
Placebo Comparator: Arm B (placebo); 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.	Other: placebo; Given PO; Other Names: PLCB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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 Measures

Outcome Measure	Measure Description	Time Frame
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.	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

Collaborators and Investigators

• Sponsor: ECOG-ACRIN Cancer Research Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Steven Libutti, Eastern Cooperative Oncology Group

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2014
• Primary Completion (Actual): July 19, 2017
• Study Completion (Actual): July 19, 2017

Study Registration Dates

• First Submitted: January 7, 2014
• First Submitted That Met QC Criteria: January 7, 2014
• First Posted (Estimated): January 9, 2014

Study Record Updates

• Last Update Posted (Actual): June 29, 2023
• Last Update Submitted That Met QC Criteria: June 14, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: everolimus; liver; randomized; metastatic pancreatic neuroendocrine tumors
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Pancreatic Diseases; Adenoma; Carcinoma, Neuroendocrine; Pancreatic Neoplasms; Adenoma, Islet Cell; Neuroendocrine Tumors; Carcinoma, Islet Cell; Insulinoma; Gastrinoma; Glucagonoma; Somatostatinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; MTOR Inhibitors; Everolimus
• Other Study ID Numbers: E2212; U10CA021115 (U.S. NIH Grant/Contract); NCI-2013-02484 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); ECOG-E2212 (Other Identifier: ECOG-ACRIN)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No