Phase III Prospective Randomized Comparison of Depot Octreotide Plus Interferon Alpha Versus Depot Octreotide Plus Bevacizumab (NSC #704865) in Advanced, Poor Prognosis Carcinoid Patients
Phase III Prospective Randomized Comparison of Depot Octreotide Plus Interferon Alpha Versus Depot Octreotide Plus Bevacizumab (NSC #704865) in Advanced, Poor Prognosis Carcinoid Patients
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.
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.
Inclusion Criteria:
Patient must have unresectable metastatic or locally advanced, low- or intermediate-grade neuroendocrine carcinoma
Patient must have high risk disease as defined by at least one of the following:
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
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:
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
Jonesboro, Arkansas 72401, United States
Burbank, California 91505, United States
Highland Park, Illinois 60035, United States
Saint Joseph, Michigan 49085, United States
Saint Joseph, Michigan 49085, United States
Saint Louis Park, Minnesota 55416, United States
Winston-Salem, North Carolina 27104, United States
Sioux Falls, South Dakota 57117-5045, United States
Silverdale, Washington 98383, United States