Brief Title
Octreotide Acetate and Recombinant Interferon Alfa-2b or Bevacizumab in Treating Patients With Metastatic or Locally Advanced, High-Risk Neuroendocrine Tumor
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
Brief Summary
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
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.
Study Phase
Phase 3
Study Type
Interventional
Primary Outcome
Central Review-based Progression-Free Survival
Secondary Outcome
Overall Survival
Condition
Atypical Carcinoid Tumor
Intervention
Bevacizumab
Study Arms / Comparison Groups
Arm I (octreotide acetate and bevacizumab)
Description: 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.
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
427
Start Date
December 1, 2007
Primary Completion Date
January 1, 2015
Eligibility Criteria
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
Gender
All
Ages
N/A - N/A
Accepts Healthy Volunteers
No
Contacts
James C Yao, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT00569127
Organization ID
NCI-2009-00778
Secondary IDs
NCI-2009-00778
Responsible Party
Sponsor
Study Sponsor
National Cancer Institute (NCI)
Study Sponsor
James C Yao, Principal Investigator, Southwest Oncology Group
Verification Date
January 2021