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Octreotide Acetate and Recombinant Interferon Alfa-2b or Bevacizumab in Treating Patients With Metastatic or Locally Advanced, High-Risk Neuroendocrine Tumor (S0518)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00569127
First received: December 5, 2007
Last updated: June 20, 2016
Last verified: June 2016
  Purpose
This randomized phase III trial is studying giving octreotide acetate together with recombinant interferon alfa-2b to see how well it works compared with giving octreotide acetate together with bevacizumab in treating patients with metastatic or locally advanced, high-risk neuroendocrine tumor. Octreotide acetate and recombinant interferon alfa-2b may interfere with the growth of tumor cells and slow the growth of cancer. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether giving octreotide acetate together with recombinant interferon alfa-2b is more effective than giving octreotide acetate together with bevacizumab in treating patients with neuroendocrine tumor.

Condition Intervention Phase
Neuroendocrine Carcinoma
Biological: Recombinant Interferon Alfa-2b
Drug: Octreotide Acetate
Biological: Bevacizumab
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase III Prospective Randomized Comparison of Depot Octreotide Plus Interferon Alpha Versus Depot Octreotide Plus Bevacizumab (NSC #704865) in Advanced, Poor Prognosis Carcinoid Patients

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Central Review-based Progression-Free Survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    From date of randomization (which is the date of registration) to date of first documentation of progression based on Central Radiological Review of the appropriate CT or MRI scans, or symptomatic deterioration (as defined in Section 10.2e)), or development of new lesions or disease not identified on CT or MRI, or death due to any cause. Patients who have a local assessment of progression based on imaging, but for whom central review does not concur, will be censored at the last Central Radiological Review date, unless subsequent scans or documentation of symptomatic deterioration provides evidence of progression. Patients last known not to have progressed are censored at the date of last contact. Patients with incomplete Central Radiological Review are censored at the date of last Central Radiological Review if patient has not progressed prior to that time.


Secondary Outcome Measures:
  • Overall Survival [ Time Frame: Up to 7 years ] [ Designated as safety issue: No ]
    From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.

  • Time to Treatment Failure [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    From date of randomization (which is the date of registration) to date of first observation of progressive disease (as defined in Section 10.2d), death due to any cause, symptomatic deterioration (as defined in Section 10.2e), or discontinuation of treatment. This has been calculated using Central-Review based progression events. Patients last known not to have failed treatment are censored at date last known not to have failed. Patients with incomplete Central Radiological Review are censored at the date of last Central Radiological Review if patient has not failed treatment prior to that time.

  • Local Progression-Free Survival (Investigator Assessed) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    From date of randomization (which is the date of registration) to date of first documentation of progression [per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) as defined in Section 10.2d] or symptomatic deterioration (as defined in Section 10.2e), or death due to any cause. Patients last known not to have progressed are censored at date of last contact. Progression (Section 10.2d) includes one or more of the following: 20% increase in the sum of the longest diameters of target measurable lesions over smallest sum observed using the same techniques as baseline; unequivocal progression of non-measurable disease in the opinion of the treating physician; appearance of new lesion/site; or death due to disease without prior documentation of progression and without symptomatic deterioration. Symptomatic deterioration (Section 10.2e) is global deterioration of health status requiring discontinuation of treatment without objective evidence of progression.

  • Objective Response (Confirmed and Unconfirmed Complete Response and Partial Response) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0): Complete Response (CR) is disappearance of all measurable and non-measurable disease, and no new lesions; Partial Response (PR) is greater than or equal to 30% decrease under baseline of the sum of longest diameters of all target measurable lesions, no unequivocal progression of non-measurable disease, and no new lesions. Confirmed response is two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration. Partial response is two or more objective statuses of PR or better a minimum of four weeks apart documented before progression or symptomatic deterioration. Unconfirmed CR is one objective status of CR documented before progression or symptomatic deterioration but not qualifying as CR or PR. Unconfirmed PR is one objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.

  • Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
    Only adverse events that are possibly, probably or definitely related to study drug are reported.


Enrollment: 427
Study Start Date: December 2007
Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (octreotide acetate and bevacizumab)
Patients receive depot octreotide acetate IM and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Octreotide Acetate
Given IM
Other Names:
  • Longastatina
  • Samilstin
  • SMS 201-995
  • SMS 201-995 AC
Biological: Bevacizumab
Given IV
Other Names:
  • Avastin
  • rhuMab-VEGF
Experimental: Arm II (octreotide acetate and recombinant interferon alfa-2b)
Patients receive octreotide acetate IM as in arm I on day 1 and recombinant interferon alfa-2b SC on days 1, 3, 5, 8, 10, 12, 15, 17, and 19. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Biological: Recombinant Interferon Alfa-2b
Given SC
Other Names:
  • Alfatronol
  • Glucoferon
  • Heberon Alfa
  • Sch 30500
  • Urifron
Drug: Octreotide Acetate
Given IM
Other Names:
  • Longastatina
  • Samilstin
  • SMS 201-995
  • SMS 201-995 AC

Detailed Description:

PRIMARY OBJECTIVES:

I. To compare central review-based progression-free survival in poor prognosis carcinoid patients treated with either depot octreotide (octreotide acetate) plus bevacizumab, or depot octreotide plus interferon (recombinant interferon alfa-2b).

II. To compare overall survival, time to treatment failure and traditionally reported progression-free survival in poor prognosis carcinoid patients treated with either depot octreotide plus bevacizumab, or depot octreotide plus interferon.

III. To compare objective response (confirmed and unconfirmed CR and PR) in poor prognosis carcinoid patients treated with either depot octreotide plus bevacizumab, or depot octreotide plus interferon.

IV. To compare the toxicity profile of patients treated with these two regimens.

V. To assess the prognostic and predictive value of VEGF expression in relation to progression-free survival and treatment effect.

VI. To compare response of 5HIAA, chromogranin A and neuronspecific enolase among patients with elevated levels at baseline between patients treated with octreotide plus interferon versus octreotide plus bevacizumab.

VII. To assess and compare the prognostic and predictive value of the combination of In-111 pentetreotide somatostatin-receptor scintigraphy (SRS) and CT vs. CT in relation to progression-free survival (PFS).

VIII. To assess and compare the prognostic and predictive value of the combination of SRS and CT vs. CT in relation to overall survival (OS) and time to treatment failure (TTF).

OUTLINE: This is a multicenter study. Patients are stratified according to site of disease (small bowel vs cecum vs appendix vs other site), disease progression after initial diagnosis (yes or no), histologic grade (low vs intermediate [atypical]), and prior octreotide acetate therapy within the past 2 months (yes vs no). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive depot octreotide acetate intramuscularly (IM) and bevacizumab intravenously (IV) over 30-90 minutes on day 1.

ARM II: Patients receive octreotide acetate IM as in arm I on day 1 and recombinant interferon alfa-2b subcutaneously (SC) on days 1, 3, 5, 8, 10, 12, 15, 17, and 19.

Treatment in both arms repeats every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 2-6 months for up to 3 years.

  Eligibility

Ages Eligible for Study:   Child, Adult, Senior
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of unresectable metastatic or locally advanced, low- or intermediate-grade neuroendocrine carcinoma, including the following subtypes:

    • Carcinoid tumor, low-grade or well differentiated neuroendocrine carcinoma
    • Atypical carcinoid tumor, intermediate-grade or moderately differentiated neuroendocrine carcinoma
  • High-risk disease as defined by at least one of the following:

    • Progressive disease
    • Refractory carcinoid syndrome while receiving octreotide acetate (i.e., defined by > 2 flushing episodes/day or > 4 bowel movements/day)
    • Atypical histology and more than 6 lesions
    • Metastatic colorectal carcinoid tumor

      • Patients with metastatic cecal or appendiceal carcinoid tumor are not eligible unless they fit other mentioned high-risk features
    • Metastatic gastric carcinoid tumor
  • Measurable disease
  • Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid tumor, or goblet cell carcinoid tumor are not eligible
  • Osseous metastasis as only site of disease
  • Medullary thyroid carcinoma or islet cell carcinoma
  • History of primary brain tumor or metastatic cancer to the brain
  • Zubrod performance status 0-2
  • Platelet count > 100,000/mm³
  • ANC > 1,500/mm³
  • Hemoglobin > 8 g/dL
  • Serum bilirubin < 1.5 times upper limit of normal (ULN)
  • SGOT and SGPT ≤ 2.5 times ULN
  • Serum creatinine < 1.5 mg/dL
  • 24-hour urine protein < 1,000 mg if urine protein:creatinine ratio > 0.5
  • PT and PTT ≤ 1.1 times ULN
  • History of hypertension must be well controlled (i.e., blood pressure < 150/90 mm Hg) on a stable regimen of antihypertensive therapy
  • Not pregnant or nursing
  • Fertile patients must use effective barrier method contraception during and for 6 months after completion of study treatment
  • History or evidence of clinically significant peripheral vascular disease (e.g., non-healing peripheral ulcers or claudication)
  • Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days
  • Bleeding diathesis or coagulopathy that results in spontaneous bleeding (in the absence of trauma) requiring red blood cell transfusion within the past 5 years
  • Serious (i.e., requiring active medical therapy with medication or medical device under the supervision of a physician) non-healing wound, ulcer, or bone fracture
  • Recent history (i.e., within the past 6 months) of any of the following arterial thromboembolic events:

    • Transient ischemic attack
    • Cerebrovascular accident
    • Unstable angina
    • Myocardial infarction
    • New York Heart Association class II or higher congestive heart failure
  • Hemoglobinopathies (e.g., Thalassemia) or any other cause of hemolytic anemia
  • Pregnant or nursing
  • Any other prior malignancy within the past 5 years except for adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer
  • Any immunologically mediated disease, including any of the following:

    • Inflammatory bowel disease (Crohn disease, ulcerative colitis)
    • Rheumatoid arthritis
    • Idiopathic thrombocytopenia purpura
    • Systemic lupus erythematosus
    • Autoimmune hemolytic anemia
    • Scleroderma
    • Severe psoriasis
  • Any serious intercurrent infections or nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this treatment
  • Psychiatric disorders rendering patient incapable of complying with the requirements of the protocol
  • Recovered from all prior therapy
  • At least 28 days since and no more than 1 prior regimen of cytotoxic chemotherapy
  • At least 28 days since prior hepatic artery embolization provided there is residual measurable disease

    • Chemoembolization is considered as 1 prior chemotherapy regimen
  • No prior interferon, bevacizumab, or any other therapy targeting VEGF or VEGF receptors (e.g., SU11248, PTK/ZK, sorafenib tosylate, or pazopanib hydrochloride)
  • Prior therapy targeting c-kit, abl, PDGFR, mTOR, and somatostatin receptors allowed
  • At least 28 days since prior radiotherapy

    • Target lesions must have shown disease progression if therapy included peptide receptor radiotherapy
  • At least 1 week since prior minor surgery
  • At least 4 weeks since prior major surgery
  • At least 21 days since prior octreotide acetate therapy
  • Concurrent full-dose anticoagulation (warfarin or low molecular weight heparin) allowed provided the following criteria are met:

    • In-range INR (e.g., between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
    • No active bleeding or pathological condition that carries a high risk of bleeding (e.g., varices)
  • No concurrent interferon to control carcinoid syndrome for patients receiving bevacizumab

    • Other supportive care medication (e.g., short acting octreotide acetate) allowed
  • No other concurrent chemotherapy, immunotherapy, radiotherapy, hepatic artery embolization, hepatic artery chemoembolization, radiofrequency ablation, or other tumor ablative procedure
  • No other investigational or commercial agents
  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: NCT00569127

  Show 506 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: James Yao Southwest Oncology Group
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00569127     History of Changes
Other Study ID Numbers: NCI-2009-00778  NCI-2009-00778  CDR0000579151  SWOG-S0518  S0518  S0518  U10CA032102 
Study First Received: December 5, 2007
Results First Received: February 18, 2016
Last Updated: June 20, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma, Neuroendocrine
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Bevacizumab
Interferons
Octreotide
Interferon-alpha
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Gastrointestinal Agents
Antineoplastic Agents, Hormonal

ClinicalTrials.gov processed this record on September 28, 2016