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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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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)
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 foregut neuroendocrine tumor