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

Study Overview
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Brief Summary
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This randomized phase III trial studies octreotide acetate and recombinant interferon alfa-2b to see how well it works compared to octreotide acetate and bevacizumab in treating patients with high-risk neuroendocrine tumors that have spread to other places in the body (metastatic) or spread from where it started to nearby tissue or lymph nodes (locally advanced). 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, may interfere with the ability of tumor cells to grow and spread. 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.

Detailed Description
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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). SECONDARY OBJECTIVES: I. 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. II. To compare objective response (confirmed and unconfirmed complete response [CR] and partial response [PR]) in poor prognosis carcinoid patients treated with either depot octreotide plus bevacizumab, or depot octreotide plus interferon. III. To compare the toxicity profile of patients treated with these two regimens. TERTIARY OBJECTIVES: I. To assess the prognostic and predictive value of vascular endothelial growth factor (VEGF) expression in relation to progression-free survival and treatment effect. II. 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. III. To assess and compare the prognostic and predictive value of the combination of In-111 pentetreotide somatostatin-receptor scintigraphy (SRS) and computed tomography (CT) vs. CT in relation to progression-free survival (PFS). IV. 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: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive octreotide acetate intramuscularly (IM) and bevacizumab intravenously (IV) over 30-90 minutes on day 1. ARM II: Patients receive octreotide acetate IM 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 up every 2-6 months for up to 3 years.

Official Title
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Phase III Prospective Randomized Comparison of Depot Octreotide Plus Interferon Alpha Versus Depot Octreotide Plus Bevacizumab (NSC #704865) in Advanced, Poor Prognosis Carcinoid Patients

Conditions
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Atypical Carcinoid Tumor, Carcinoid Tumor, Colorectal Neuroendocrine Tumor G1, Gastric Neuroendocrine Tumor G1, Neuroendocrine Neoplasm

Intervention / Treatment
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* Biological: Bevacizumab
* Other: Laboratory Biomarker Analysis
* Drug: Octreotide Acetate
* Biological: Recombinant Interferon Alfa-2b


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have unresectable metastatic or locally advanced, low- or intermediate-grade neuroendocrine carcinoma NOTE: pathology report must state one of the following: carcinoid, low-grade or well-differentiated neuroendocrine carcinoma, atypical carcinoid, intermediate-grade or moderately differentiated neuroendocrine carcinoma; patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, or goblet cell carcinoid are not eligible; patient must not have osseous metastasis as only site of disease; patients with medullary thyroid carcinoma or islet cell carcinoma are not eligible; if pathology report states only neuroendocrine carcinoma, pathology subtype must be reconfirmed Occasionally, it is not possible to establish tumor grade on fine-needle aspiration (FNA) cytology material; if a new biopsy is needed, a core needle biopsy should be obtained whenever possible Patient must have high risk disease as defined by at least one of the following: Progressive disease Refractory carcinoid syndrome while receiving octreotide (defined by > 2 flushing episodes/day or > 4 bowel movements/day) Atypical histology and more than 6 lesions Metastatic colorectal carcinoid; patients with metastatic cecal or appendiceal carcinoid tumor are not eligible unless the tumors fit into one of the other high-risk categories (a, b, or c above) Metastatic gastric carcinoid Patient must have measurable disease; CT or magnetic resonance imaging (MRI) used for tumor measurement must have been completed within 28 days prior to registration; X-rays, scans or other tests for assessment of non-measurable disease must have been performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form; these scans also must be submitted for central radiology review Institutions are required to submit CT/MRI scans and archived tissue for pathology review; furthermore, institutions are required to seek additional patient consent for submission of octreotide scans, and submission of blood and use of archived tissue for correlative studies If patient consents to the submission of octreotide scans, the patient must also be registered to Registration Step 2 Patient may have had up to one prior regimen of cytotoxic chemotherapy; at least 28 days must have elapsed since completion of prior therapy, and patient must have recovered from all effects Patient may have had prior hepatic artery embolization; at least 28 days must have elapsed since embolization and there must be residual measurable disease; chemoembolization will be considered as one prior chemotherapy regimen Patient must not have received prior interferon, bevacizumab or any other therapy targeting VEGF or VEGF receptors Patient may have received prior therapy targeting stem cell factor receptor (c-kit), abelson murine leukemia viral oncogene homolog 1 (abl), platelet-derived growth factor receptor (PDGFR), mammalian target of rapamycin (mTOR), and somatostatin receptors (not counted toward prior cytotoxic chemotherapy) Prior radiation is allowed; there must be measurable disease; if prior therapies include peptide receptor radiotherapy, the target lesion(s) must have shown disease progression; at least 28 days must have elapsed since completion of prior therapy, and patient must have recovered from all effects Patients must have recovered from any prior surgery; one week must have elapsed from the time of a minor surgery and 4 weeks from major surgery At least 21 days must have elapsed since any prior octreotide LAR depot treatment Patient must have a Zubrod performance status of 0-2 Absolute neutrophil count (ANC) > 1,500/mcl Hemoglobin > 8 g/dl Platelets > 100,000/mcl Serum bilirubin < 1.5 x institutional upper limit of normal (IULN) Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) =< 2.5 x IULN Serum creatinine < 1.5 mg/dL Urine protein must be screened by urine analysis for Urine Protein Creatinine (UPC) ratio; for UPC ratio > 0.5, 24-hour urine protein must be obtained and the level must be < 1,000 mg for patient enrollment; these results must be obtained within 28 days prior to registration Note: UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion - a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm Patients not on anticoagulation must have prothrombin time (PT) and partial thromboplastin time (PTT) =< 1.1 x lULN obtained within 28 days prior to registration; patients on full-dose anticoagulation (warfarin or low molecular weight heparin) are eligible provided that both of the following criteria are met: The patient has an in-range international normalized ratio (INR) (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin The patient has no active bleeding or pathological condition that carries a high risk of bleeding such as varices Patient must not have history or evidence of clinically significant peripheral vascular disease such as non-healing peripheral ulcers or claudication Patient must not have a history of primary brain tumor or metastatic cancer to the brain; brain imaging studies are not required for eligibility if the patient has no neurological signs or symptoms; if brain imaging studies are performed, they must be negative for disease Patient must not have a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to registration Patient must not have history within the past 5 years or presence of bleeding diathesis or coagulopathy that results in spontaneous bleeding (in the absence of trauma) requiring packed red blood cells (pRBC) transfusion Patient must not have a serious (requiring active medical therapy with medication or medical device under the supervision of a physician) non-healing wound, ulcer, or bone fracture Patient must not have recent history (within 6 months prior to registration) of these arterial thromboembolic events: transient ischemic attack, cerebrovascular accident, unstable angina, myocardial infarction, or New York Heart Association grade II or higher congestive heart failure Patients with a history of hypertension must be well-controlled (blood pressure < 150/90), on a stable regimen of antihypertensive therapy Patient must not have hemoglobinopathies (e.g., Thalassemia) or any other cause of hemolytic anemia Patient must not plan to use any other concurrent chemotherapy, immunotherapy, hepatic artery embolization, hepatic artery chemoembolization, radiofrequency ablation, other tumor ablative procedure or radiotherapy while on protocol treatment Patient must not be pregnant or nursing because bevacizumab may be harmful to the developing fetus and newborn; male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout protocol treatment and for up to 6 months following discontinuation of bevacizumab No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any other cancer from which the patient has been disease free for five years All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines At the time of patient registration, the treating institution's name and identification (ID) number must be provided to the Data Operations Center in Seattle in order to ensure that the current (within 365 days) date of institutional re view board approval for this study has been entered into the data base REGISTRATION STEP 2 - SPECT SUBSTUDY Patient must have registered to the main study Patient must have consented to the submission of octreotide scans An octreotide scan obtained within 28 days prior to Registration Step 1 must be available for submission
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (octreotide acetate and bevacizumab)<br>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. | Biological: Bevacizumab<br>* Given IV<br>* Other names: Zirabev;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Octreotide Acetate<br>* Given IM<br>* Other names: SMS 201-995 AC;|
| Experimental: Arm II (octreotide acetate and recombinant interferon alfa-2b)<br>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. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Octreotide Acetate<br>* Given IM<br>* Other names: SMS 201-995 AC;Biological: Recombinant Interferon Alfa-2b<br>* Given SC<br>* Other names: Viraferon;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Central Review-based Progression-Free Survival | 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. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | 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. | Up to 7 years | 
| Time to Treatment Failure | 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. | Up to 3 years | 
| Local Progression-Free Survival (Investigator Assessed) | 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. | Up to 3 years | 
| Objective Response (Confirmed and Unconfirmed Complete Response and Partial Response) | 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. | Up to 3 years | 
| Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Only adverse events that are possibly, probably or definitely related to study drug are reported. | Up to 3 years |