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

• Sponsor: ECOG-ACRIN Cancer Research Group (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02031536
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 2
• Location: 1
• Arms: 2
• Actual Duration (Months): 42
• Patients Per Site Per Month: 0

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Gastrinoma; Glucagonoma; Insulinoma; Liver Metastases; Pancreatic Polypeptide Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma	Drug: everolimus; Other: placebo	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. 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.

2. 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 Design

• Study Type: Interventional
• Actual Enrollment: 2 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Jan 17, 2014
• Actual Primary Completion Date: Jul 19, 2017
• Actual Study Completion Date: Jul 19, 2017

Arms and Interventions

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: 42-O-(2-hydroxy)ethyl rapamycin Afinitor RAD001
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

Outcome Measures

Primary Outcome Measures

1. Disease Free Survival (DFS) [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]

   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

1. Overall Survival (OS) [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]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ecog-Acrin	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• ECOG-ACRIN Cancer Research Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Steven Libutti, Eastern Cooperative Oncology Group

Study Documents (Full-Text)

• Study Protocol: Study protocol - Apr 21, 2014
• Informed Consent Form - Apr 21, 2014
• Study Protocol and Statistical Analysis Plan: 9. Statistical Considerations - Apr 21, 2014

More Information

Publications

None provided.

• Responsible Party: ECOG-ACRIN Cancer Research Group
• ClinicalTrials.gov Identifier: NCT02031536
• Other Study ID Numbers: E2212; NCI-2013-02484; ECOG-E2212; U10CA021115
• First Posted: Jan 9, 2014
• Last Update Posted: Dec 2, 2020
• Last Verified: Dec 1, 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Keywords provided by ECOG-ACRIN Cancer Research Group: everolimus; randomized; metastatic pancreatic neuroendocrine tumors; liver
• Additional relevant MeSH terms: Neuroendocrine Tumors; Insulinoma; Carcinoma, Islet Cell; Gastrinoma; Glucagonoma; Somatostatinoma; Everolimus

Study Results

Participant Flow

Recruitment Details	This study was activated on January 17, 2014 and closed to accrual on March 30, 2015. Two patients, both from Stanford University, were randomized to the trial.

Arm/Group Title	Arm A (Everolimus)	Arm B (Placebo)
Arm/Group 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. everolimus: Given PO	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. placebo: Given PO
Period Title: Overall Study
STARTED	2	0
COMPLETED	1	0
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Arm A (Everolimus)	Arm B (Placebo)	Total
Arm/Group 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. everolimus: Given PO	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. placebo: Given PO	Total of all reporting groups
Overall Participants	2	0	2
Age, Customized (Count of Participants)
Age between 45-49	2 100%	0 NaN	2 100%
Sex: Female, Male (Count of Participants)
Female	1 50%	0 NaN	1 50%
Male	1 50%	0 NaN	1 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 NaN	0 0%
Asian	1 50%	0 NaN	1 50%
Native Hawaiian or Other Pacific Islander	0 0%	0 NaN	0 0%
Black or African American	0 0%	0 NaN	0 0%
White	1 50%	0 NaN	1 50%
More than one race	0 0%	0 NaN	0 0%
Unknown or Not Reported	0 0%	0 NaN	0 0%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All enrolled patients

Arm/Group Title	Arm A (Everolimus)	Arm B (Placebo)
Arm/Group 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. everolimus: Given PO	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. placebo: Given PO
Measure Participants	2	0
Median (95% Confidence Interval) [years]	1.3

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All enrolled patients

Arm/Group Title	Arm A (Everolimus)	Arm B (Placebo)
Arm/Group 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. everolimus: Given PO	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. placebo: Given PO
Measure Participants	2	0
Median (95% Confidence Interval) [years]	2.05

Adverse Events

Time Frame	Adverse events were assessed at the end of each cycle (1 cycle=4 weeks) and at 30 days after the completion of protocol therapy
Adverse Event Reporting Description	Only grades 4-5 hematologic events and grades 3-5 non-hematologic events were reportable on this study.
Arm/Group Title	Arm A (Everolimus)		Arm B (Placebo)
Arm/Group 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. everolimus: Given PO		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. placebo: Given PO
All Cause Mortality
	Arm A (Everolimus)		Arm B (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/2 (50%)		0/0 (NaN)
Serious Adverse Events
	Arm A (Everolimus)		Arm B (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/2 (50%)		0/0 (NaN)
Investigations
Aspartate aminotransferase increase	1/2 (50%)		0/0 (NaN)
Neutrophil count decrease	1/2 (50%)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Arm A (Everolimus)		Arm B (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.