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

Brief Title

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

Official Title

Randomized Phase II Study of Everolimus Alone Versus Everolimus Plus Bevacizumab in Patients With Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors

Brief Summary

      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.
    

Detailed Description

      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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Progression Free Survival

Secondary Outcome

 Overall Response Rate

Condition

Advanced Pancreatic Neuroendocrine Tumor

Intervention

Bevacizumab

Study Arms / Comparison Groups

 Arm I (octreotide acetate and everolimus)
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

150

Start Date

October 15, 2010


Primary Completion Date

September 1, 2014

Eligibility 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 virus (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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Matthew H Kulke, , 

Location Countries

Canada

Location Countries

Canada

Administrative Informations


NCT ID

NCT01229943

Organization ID

NCI-2011-02609

Secondary IDs

NCI-2011-02609

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Matthew H Kulke, Principal Investigator, Alliance for Clinical Trials in Oncology


Verification Date

August 2021