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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01229943
First received: October 27, 2010
Last updated: August 15, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Gastrinoma
Glucagonoma
Insulinoma
Pancreatic Alpha Cell Adenoma
Pancreatic Alpha Cell Carcinoma
Pancreatic Beta Islet Cell Adenoma
Pancreatic Beta Islet Cell Carcinoma
Pancreatic Delta Cell Adenoma
Pancreatic Delta Cell Carcinoma
Pancreatic G-cell Adenoma
Pancreatic G-cell Carcinoma
Pancreatic Polypeptide Tumor
Recurrent Islet Cell Carcinoma
Recurrent Pancreatic Cancer
Somatostatinoma
Stage III Pancreatic Cancer
Stage IV Pancreatic Cancer
Drug: everolimus
Drug: octreotide acetate
Biological: bevacizumab
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase II Study of Everolimus Alone Versus Everolimus Plus Bevacizumab in Patients With Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • PFS [ Time Frame: From study entry to the date of documented progression or death from any cause, up to 3 years ] [ Designated as safety issue: No ]
    The Kaplan-Meier will be used to estimate the PFS curves within each treatment arm.


Secondary Outcome Measures:
  • Response rate measured by Response Evaluation Criteria in Solid Tumors [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
  • Overall survival (OS) [ Time Frame: From registration to time of death, assessed up to 3 years ] [ Designated as safety issue: No ]
    The Kaplan-Meier will be used to estimate the OS curves within each treatment arm.


Estimated Enrollment: 138
Study Start Date: October 2010
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (octreotide acetate and everolimus)
Patients receive everolimus PO QD on days 1-28 and octreotide acetate IM on day 1.
Drug: everolimus
Given PO
Other Names:
  • 42-O-(2-hydroxy)ethyl rapamycin
  • Afinitor
  • RAD001
Drug: octreotide acetate
Given IM
Other Names:
  • Longastatin
  • Longastatina
  • Samilstin
  • SMS 201-995
Experimental: Arm II (octreotide acetate, everolimus, and bevacizumab)
Patients receive everolimus and octreotide acetate as in Arm I. Patients also receive bevacizumab IV on days 1 and 15.
Drug: everolimus
Given PO
Other Names:
  • 42-O-(2-hydroxy)ethyl rapamycin
  • Afinitor
  • RAD001
Drug: octreotide acetate
Given IM
Other Names:
  • Longastatin
  • Longastatina
  • Samilstin
  • SMS 201-995
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF

Detailed Description:

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

I. To compare 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologic documentation of well-differentiated or moderately differentiated neuroendocrine tumor from either a primary or metastatic site

    • If different histologic classification schemes are used, equivalent histologic classifications (for example "grade 1", "low-grade", or "intermediate-grade") are allowed
    • Patients with poorly differentiated neuroendocrine carcinoma or small cell carcinoma are excluded
    • Documentation from a metastatic disease site is sufficient if there is clinical evidence of a pancreatic primary site
  • Locally unresectable or metastatic disease
  • Patients must have either histologic documentation of a pancreatic primary site, or clinical evidence of a pancreatic neuroendocrine primary tumor as determined by the treating physician

    • Patients with neuroendocrine tumors (e.g., gastrinoma, VIPoma) in whom a pancreatic or peripancreatic primary site is strongly suspected are also eligible
  • Patients must have evidence of disease (measurable or non-measurable) with evidence of progression within the past 12 months
  • Measurable disease:

Lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 2 cm with conventional techniques or as >= 1 cm with spiral computed tomography (CT) scan

  • Non-measurable disease:

All other lesions, including small lesions (longest diameter < 20 mm with conventional techniques or < 10 mm with spiral CT scan) and truly non-measurable lesions; lesions that are considered non-measurable include the following:

  • Bone lesions
  • Leptomeningeal disease
  • Ascites
  • Pleural/pericardial effusion
  • Inflammatory breast disease
  • Lymphangitis cutis/pulmonis
  • Abdominal masses that are not confirmed and followed by imaging techniques
  • Cystic lesions

    • No prior treatment with bevacizumab, everolimus, or other mammalian target of rapamycin (mTOR) inhibitors
    • Other prior treatments, including but not limited to prior cytotoxic chemotherapy, alpha interferon, tyrosine kinase inhibitors, external beam radiation therapy, and radiopeptide therapy are allowed
  • There is no limit on the number of prior treatment regimens
  • Any prior treatment (with the exception of octreotide) must be completed at least 4 weeks prior to initiation of treatment

    • Prior treatment with embolization or ablative therapies is allowed if measurable disease remains outside of the treated area
  • There is no limit on the prior number of procedures

    • Treatment with somatostatin analogs is a requirement of the study
  • Patients receiving octreotide at the time of study entry may continue at the same dose level for the duration of the study
  • Patients not receiving octreotide will initiate treatment according to study guidelines
  • Prior progression on somatostatin analogs or a negative octreotide scan does not exclude patient participation in this study

    • Patients should have completed any major surgery >= 4 weeks from start of treatment
  • Patients must have completed any minor surgery >= 2 weeks prior to start of treatment
  • Patients must have fully recovered from the procedure
  • Insertion of a vascular access device is not considered major or minor surgery

    • Patients should not receive immunization with attenuated live vaccines within one week prior to registration or during protocol therapy
    • No concurrent condition resulting in immune compromise, including chronic treatment with corticosteroids or other immuno suppressive agents
    • No active or severe liver disease (e.g., acute or chronic hepatitis, cirrhosis); no positive anti-hepatitis B (HBV); HBV seropositive patients (hepatitis B surface antigen [HBsAg] positive) are eligible if they are closely monitored for evidence of active HBV infection by HBV deoxyribonucleic acid (DNA) testing, and they agree to receive suppressive therapy with lamivudine or other HBV-suppressive therapy until at least 4 weeks after the last dose of everolimus; patients who are hepatitis C antibody positive are eligible provided that hepatitis C viral load (hepatitis C ribonucleic acid [RNA]) is undetectable
    • No clinical evidence of brain metastases or carcinomatous meningitis
    • No history of gastrointestinal (GI) perforation within 12 months prior to registration
    • No history of clinically significant bleeding episodes
    • Patients on therapeutic anticoagulation are eligible for the study provided that they are on a stable dose of anticoagulants
    • No uncontrolled diabetes mellitus
    • Patients with a history of severely impaired lung function as defined as spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) that is 50% of the normal predicted value and/or oxygen (O2) saturation that is 88% or less at rest on room air are excluded
    • Patients with fasting serum cholesterol >= 300 mg/dL OR >= 7.75 mmol/L AND fasting triglycerides >= 2.5 X upper limit of normal (ULN) should initiate lipid-lowering medications with the goal of achieving levels below these thresholds
    • No history of intolerance or allergies to octreotide
    • Patients with a history of hypertension must be adequately controlled (baseline blood pressure [BP] < 150/90 mm Hg) on antihypertensives
    • No current congestive heart failure (New York Heart Association class II, III, or IV)
    • No symptomatic arterial peripheral vascular disease
    • No history of aortic aneurysm, aortic dissection, angina, myocardial infarction, stroke, or other arterial thrombotic events within 6 months of registration
    • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
    • Women must not be pregnant or lactating; both men and women of childbearing potential must be advised of the importance of using effective birth control measures during the course of the study
    • Granulocytes >= 1,500/uL
    • Platelets >= 100,000/uL
    • Creatinine =< 1.5 x upper limit of normal
    • Bilirubin =< 1.5 x upper limit of normal
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (=< 5 x upper limit of normal if liver metastases present)
    • Urine protein =< 1+ OR urine creatinine ratio =< 1 (by urinalysis)
  • If urine protein creatinine (UPC) ratio is > 1 on urinalysis, then 24-hour urine collection for protein must be obtained and level must be < 1,000 mg for patient enrollment
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01229943

  Show 402 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Matthew Kulke Alliance for Clinical Trials in Oncology
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01229943     History of Changes
Other Study ID Numbers: NCI-2011-02609, NCI-2011-02609, CDR0000687459, CALGB-80701, CALGB 80701, CALGB-80701, U10CA180821, U10CA031946
Study First Received: October 27, 2010
Last Updated: August 15, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Adenoma
Carcinoma
Gastrinoma
Zollinger-Ellison Syndrome
Glucagonoma
Insulinoma
Adenoma, Islet Cell
Pancreatic Neoplasms
Somatostatinoma
Neuroendocrine Tumors
Carcinoma, Islet Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Paraneoplastic Endocrine Syndromes
Paraneoplastic Syndromes
Gastrointestinal Neoplasms
Gastrointestinal Diseases
Intestinal Diseases
Peptic Ulcer
Stomach Diseases
Carcinoma, Neuroendocrine
Neuroectodermal Tumors

ClinicalTrials.gov processed this record on August 18, 2014