Symptoms and General Pathology

All Conditions

Neoplasms

Digestive System Diseases

Gland and Hormone Related Diseases

Substance Related Disorders

Rare Diseases

Recurrence

Neuroendocrine Tumors

Carcinoid Tumor

Intestinal Neoplasms

Pancreatic Neoplasms

Stomach Neoplasms

Syndrome

Malignant Carcinoid Syndrome

Serotonin Syndrome

Gastrointestinal Neoplasms

Digestive System Neoplasms

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Adenocarcinoma

Carcinoma

Neoplasms, Glandular and Epithelial

Gastrointestinal Diseases

Intestinal Diseases

Endocrine Gland Neoplasms

Pancreatic Diseases

Endocrine System Diseases

Stomach Diseases

Neuroendocrine Tumor

Gastro-enteropancreatic Neuroendocrine Tumor

Pancreatic Cancer

Stomach Cancer

Carcinoid Syndrome

Neuroepithelioma

Patients receive pazopanib hydrochloride PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA during screening. Patients also undergo CT, MRI, and chest x-ray throughout the trial. Patients may optionally undergo blood sample collection during screening and on study.

Patients receive placebo PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. At the time of progressive disease, patients may cross-over to Arm I. Patients undergo ECHO or MUGA during screening. Patients also undergo CT, MRI, and chest x-ray throughout the trial. Patients may optionally undergo blood sample collection during screening and on study.

Biospecimen Collection

Computed Tomography

Echocardiography

Laboratory Biomarker Analysis

Magnetic Resonance Imaging

Multigated Acquisition Scan

Pazopanib Hydrochloride

Placebo Administration

Quality-of-Life Assessment

X-Ray Imaging

Emily K Bergsland

This randomized phase II trial studies how well pazopanib hydrochloride works in treating patients with carcinoid tumors that are growing, spreading, or getting worse. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVE:

I. For patients with progressive carcinoid tumors, progression-free survival (PFS defined by central review according to Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1) will be compared between patients randomized to treatment with pazopanib (pazopanib hydrochloride) versus placebo.

SECONDARY OBJECTIVES:

I. Overall survival (OS) will be compared between treatment arms. II. Objective response rate, duration of response, and time to treatment failure will be compared between treatment arms.

III. Progression free survival (PFS) as assessed by central radiology review and local radiology review will be compared overall and within treatment arms.

IV. Safety and tolerability of treatment with pazopanib/placebo will be evaluated within each treatment arm.

V. PFS and other indicators of efficacy will be estimated in patients who crossover to pazopanib from placebo.

VI. To determine the turn-around time for timely adjudicated central review. VII. To characterize the nature of discordance between local and central radiology review in assessment of progression.

VIII. To characterize the type and rate of progression in carcinoid (at study entry, on-study, and at progression).

IX. To develop new methods for modeling carcinoid growth and detecting treatment effects, and to perform simulations that advance new clinical trial designs to apply to future trials of carcinoid therapeutics.

X. To assess for differences in quality of life (QOL)-related domains between the two treatment groups (pazopanib versus placebo).

XI. To determine if the more brief measures of QOL-related domains provide comparable information to that which is provided by the longer assessments (European Organization for Research and Treatment of Cancer \[EORTC\], neuroendocrine tumors \[NET\]21).

XII. To provide validation data for the EORTC NET21 module in terms of responsiveness over time and differences across arms.

XIII. To determine whether components of the plasma angiome panel that have been shown to be predictive previously (interleukin-6 \[IL-6\] and vascular endothelial growth factor \[VEGF\]-D) are predictive of a therapeutic advantage for pazopanib treatment in baseline samples from the patients treated on A021202.

XIV. To determine whether other components of the plasma angiome panel tested (not IL-6 and VEGF-D) are predictive of a therapeutic advantage for pazopanib treatment in baseline samples from the patients treated on A021202.

XV. To evaluate the changes in the plasma angiome markers after treatment with or without pazopanib over time.

EXPLORATORY OBJECTIVES:

I. PFS at 6 months will be estimated within each treatment arm. II. Biochemical response (for chromogranin A, defined as a decrease of 50% or more in chromogranin A levels from baseline and for 5-hydroxyindoleacetic acid \[5-HIAA\], defined as a decrease of 50% or more in urinary 5-HIAA levels from baseline) will be compared between treatment arms among patients with elevated baseline levels of chromogranin A (CGA) and 5-HIAA.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening. Patients also undergo computed tomography (CT), magnetic resonance imaging (MRI), and chest x-ray throughout the trial. Patients may optionally undergo blood sample collection during screening and on study.

ARM II: Patients receive placebo PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. At the time of progressive disease, patients may cross-over to Arm I. Patients undergo ECHO or MUGA during screening. Patients also undergo CT, MRI, and chest x-ray throughout the trial. Patients may optionally undergo blood sample collection during screening and on study.

After completion of study treatment, patients are followed up every 3-6 months for 5 years.

Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors

Prospective Randomized Phase II Trial of Pazopanib (NSC #737754) Versus Placebo in Patients With Progressive Carcinoid Tumors

Kaplan-Meier methods will be used including calculations of 95% confidence intervals.

Biochemical response (for chromogranin A, defined as a decrease of 50% or more in chromogranin A levels from baseline, and for 5-hydroxyindoleacetic acid \[5-HIAA\], defined as a decrease of 50% or more in urinary 5-HIAA levels from baseline) will be compared between treatment arms among patients with elevated baseline levels of serum chromogranin A (CGA) and 5-HIAA.

PFS will be measured from date of patient entry until documented progression of disease as determined by central review or death from any cause. If a patient does not have a documented date of progression or death, then PFS will be censored at the date of last adequate assessment. PFS will be estimated within treatment arm using the Kaplan-Meier method. Progression is defined as any new lesion or increase by ≥20% of previously involved sites from nadir based on RECIST criteria.

The best response per RECIST 1.1 criteria of participants receiving randomized treatment assignment. Complete response (CR): Disappearance of all evidence of disease, Partial response (PR): Regression of measurable disease and no new sites, Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum diameters while on study. Progressive disease (PD): Any new lesion or increase by ≥20% of previously involved sites from nadir. Note that those considered evaluable for best response here were those who had disease measurements while on treatment. Those who discontinued therapy early prior to a disease evaluation were not included.

Overall survival (OS) will be measured from randomization until death from any cause. A patient who is alive at the time of the statistical analysis will be considered censored at the last date of known contact. OS will be estimated by the Kaplan-Meier method within each treatment arm.

Duration of response is defined as the time from documented response to time of progression and/or death. This time-to-event outcome will be summarized descriptively using the methods of Kaplan and Meier to characterize the cohort and distribution of this outcome.

Time to treatment failure is defined as the time from randomization to the time that treatment is terminated, including the reasons of disease progression, adverse events, withdrawal from study, or death. This time-to-event outcome will be evaluated using the methods of Kaplan and Meier.

National Cancer Institute (NCI)

Patients receive 800 mg pazopanib hydrochloride PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Arm I (Pazopanib Hydrochloride)

Patients receive 800 mg placebo PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. At the time of progressive disease, patients may cross-over to Arm I.

Arm II (Placebo)

Participants in Arm II (Placebo) who crossed over to receive pazopanib hydrochloride.

Placebo Crossover

Total

Age, Continuous

Sex: Female, Male

Race (White vs Non-White)

Race/Ethnicity, Customized

Eastern Cooperative Oncology Group PS Scale: 0)Fully active, able to carry on all pre-disease performance without restriction; 1)Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2)Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 3)Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4)Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.

ECOG Performance status

Emily Bergsland, M.D.

Progression-free Survival (PFS)

Per protocol, patients who crossover from placebo to active therapy at the time of progression will be followed for a second progression unless they withdraw from treatment for other reasons; in that case they will be followed for toxicity and survival only; thus response data are not available for "Placebo Crossover" group.

Best Response

This trial only has two arms ((Arm I (pazopanib hydrochloride) and Arm II (placebo)) that were analyzed. Pazopanib hydrochloride and Pazopanib are synonyms and Pazopanib was deleted. Per protocol, OS will be estimated by the Kaplan-Meier method within each treatment arm. OS for placebo patients who crossed over is not a specified outcome measure.

Overall Survival

Duration of Response for the Subset of Patients With a Confirmed Complete Response or Partial Response

Time to Treatment Failure

Time to Second Progression for Patients Who Crossover From Placebo to Active Therapy

PFS Within Each Arm

Biochemical Response

Overall Study

All Drugs and Chemicals

Antineoplastic Agents

Anti-Infective Agents

Gastrointestinal Agents

Antibodies

Antibodies, Monoclonal

Bevacizumab

Immunoglobulins

Immunoglobulin G

Endothelial Growth Factors

Mitogens

Interferons

Immunoglobulins, Intravenous

Octreotide

Interferon-alpha

Interferon alpha-2

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Immunologic Factors

Antiviral Agents

Antineoplastic Agents, Hormonal

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.

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.

Octreotide Acetate

Recombinant Interferon Alfa-2b

James C Yao

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.

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

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

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.

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.

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.

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.

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.

Only adverse events that are possibly, probably or definitely related to study drug are reported.

Eligible patients who received treatment and were assessed for adverse events are included in the adverse event summaries. Eleven patients did not start protocol treatment due to: patient refusal (6), financial reasons (3), and worsening condition/progression (2). None were assessable for adverse events and thus are not included in this analysis.

Patients receive 20 mg depot octreotide acetate IM and 15 mg/kg bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Octreotide, Bevacizumab

Patients receive 20 mg depot octreotide acetate IM on day 1 and 5 million units interferon alpha-2b three times per week (Days 1, 3, 5, 8, 10, 12, 15, 17, 19 of each cycle). Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Octreotide, Interferon Alpha-2b

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Small bowel, cecum, appendix

Other sites

Disease Site

Progression after Initial Diagnosis

Intermediate (atypical)

Histologic Grade

Within 2 months prior to registration

None within 2 months prior to registration

Prior Octreotide

SWOG Statistician

According to the intent-to-treat principle, all eligible patients will be included in this analysis according to the randomized treatment assignment, regardless of actual treatments received.

According to the intent-to-treat principle, all eligible patients were included in the analysis according to the randomized treatment assignment, regardless of actual treatments received.

Central Review-based Progression-Free Survival

Local Progression-Free Survival (Investigator Assessed)

Complete Response

Partial Response

Unconfirmed Complete Response

Unconfirmed Partial Response

Stable/No Resposne

Increasing Disease

Symptomatic Deterioration

Assessment Inadequate

All eligible patients with measurable disease will be included in this analysis according to the randomized treatment assignment.

Objective Response (Confirmed and Unconfirmed Complete Response and Partial Response)

ALT, SGPT (serum glutamic pyruvic transaminase)

AST, SGOT

Albumin, serum-low (hypoalbuminemia)

Alkaline phosphatase

Allergic reaction/hypersensitivity

Anorexia

Ataxia (incoordination)

Auditory/Ear-Other (Specify)

Bilirubin (hyperbilirubinemia)

CNS cerebrovascular ischemia

Cardiac troponin I (cTnI)

Cardiac-ischemia/infarction

Cardiopulmonary arrest, cause unknown (non-fatal)

Cholecystitis

Cognitive disturbance

Colitis

Constipation

Creatinine

Dehydration

Dental: periodontal disease

Diarrhea

Dizziness

Dyspnea (shortness of breath)

Edema: limb

Fatigue (asthenia, lethargy, malaise)

Fever in absence of neutropenia, ANC lt1.0x10e9/L

Fistula, GI - Colon/cecum/appendix

Fistula, GU - Vagina

Glucose, serum-high (hyperglycemia)

Hearing: pts w/o audiogram not enroll monitor prgm

Heartburn/dyspepsia

Hemoglobin

Hemorrhage, CNS

Hemorrhage, GI - Rectum

Hemorrhage, GI - Upper GI NOS

Hemorrhage, pulmonary/upper respiratory - Nose

Hemorrhage/Bleeding-Other (Specify)

Hot flashes/flushes

Hydrocephalus

Hypertension

Hypotension

Hypoxia

INR (of prothrombin time)

Ileus, GI (functional obstruction of bowel)

Inf (clin/microbio) w/Gr 3-4 neuts - Blood

Eligible patients who received any treatment and were assessed for adverse events are included in this summary. Eleven patients did not start protocol treatment due to: patient refusal (6), financial reasons (3), and worsening condition/progression (2). None were assessable for adverse events and thus are not included in this analysis.

Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors	NCT01841736	Foregut Neuroen... Hindgut Neuroen... Metastatic Dige... Metastatic Neur... Midgut Neuroend... Neuroendocrine ... Recurrent Diges... Regional Digest...	Biospecimen Col... Computed Tomogr... Echocardiograph... Laboratory Biom... Magnetic Resona... Multigated Acqu... Pazopanib Hydro... Placebo Adminis... Quality-of-Life... X-Ray Imaging	18 Years -	National Cancer Institute (NCI)
Octreotide Acetate and Recombinant Interferon Alfa-2b or Bevacizumab in Treating Patients With Metastatic or Locally Advanced, High-Risk Neuroendocrine Tumor	NCT00569127	Colorectal Neur... Gastric Neuroen... Neuroendocrine ... Neuroendocrine ... Neuroendocrine ...	Bevacizumab Laboratory Biom... Octreotide Acet... Recombinant Int...	-	National Cancer Institute (NCI)
Octreotide Acetate and Recombinant Interferon Alfa-2b or Bevacizumab in Treating Patients With Metastatic or Locally Advanced, High-Risk Neuroendocrine Tumor	NCT00569127	Colorectal Neur... Gastric Neuroen... Neuroendocrine ... Neuroendocrine ... Neuroendocrine ...	Bevacizumab Laboratory Biom... Octreotide Acet... Recombinant Int...	-	National Cancer Institute (NCI)
Testing Cabozantinib in Patients With Advanced Pancreatic Neuroendocrine and Carcinoid Tumors	NCT03375320	Carcinoid Tumor Functioning Pan... Intermediate Gr... Locally Advance... Locally Advance... Locally Advance... Locally Advance... Locally Advance... Low Grade Lung ... Lung Neuroendoc... Lung Neuroendoc... Metastatic Dige... Metastatic Dige... Metastatic Lung... Metastatic Lung... Metastatic Panc... Metastatic Panc... Metastatic Thym... Neuroendocrine ... Neuroendocrine ... Non-Functioning... Pancreatic Sero... Thymic Neuroend... Unresectable Di... Unresectable Di... Unresectable Lu... Unresectable Pa... Unresectable Th...	Cabozantinib S-... Computed Tomogr... Magnetic Resona... Placebo Adminis... Quality-of-Life... X-Ray Imaging	18 Years -	National Cancer Institute (NCI)
Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors	NCT01841736	Foregut Neuroen... Hindgut Neuroen... Metastatic Dige... Metastatic Neur... Midgut Neuroend... Neuroendocrine ... Recurrent Diges... Regional Digest...	Biospecimen Col... Computed Tomogr... Echocardiograph... Laboratory Biom... Magnetic Resona... Multigated Acqu... Pazopanib Hydro... Placebo Adminis... Quality-of-Life... X-Ray Imaging	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for neuroendocrine tumor g2