Testing Cabozantinib In Patients With Advanced Pancreatic Neuroendocrine And Carcinoid Tumors

Study Overview

Testing Cabozantinib in Patients With Advanced Pancreatic Neuroendocrine and Carcinoid Tumors

This phase III trial studies cabozantinib to see how well it works compared with placebo in treating patients with neuroendocrine or carcinoid tumors that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Cabozantinib is a chemotherapy drug known as a tyrosine kinase inhibitor, and it targets specific tyrosine kinase receptors, that when blocked, may slow tumor growth.

PRIMARY OBJECTIVES: I. To determine whether cabozantinib (cabozantinib S-malate) can significantly improve progression-free survival (PFS) compared to placebo in patients with advanced pancreatic neuroendocrine tumors (NET) whose disease has progressed after prior therapy. II. To determine whether cabozantinib can significantly improve progression-free survival (PFS) compared to placebo in patients with advanced carcinoid tumors whose disease has progressed after prior therapy. SECONDARY OBJECTIVES: I. To determine whether cabozantinib can significantly improve overall survival (OS) compared to placebo in patients with advanced pancreatic NET whose disease has progressed after prior therapy. II. To determine whether cabozantinib can significantly improve overall survival (OS) compared to placebo in patients with advanced carcinoid tumors whose disease has progressed after prior therapy. III. To evaluate safety and tolerability of cabozantinib versus placebo in patients with advanced pancreatic NET using Common Terminology Criteria for Adverse Events (CTCAE) and Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). IV. To evaluate safety and tolerability of cabozantinib versus placebo in patients with advanced carcinoid tumors using CTCAE and PRO-CTCAE. V. To evaluate the overall radiographic response rate of cabozantinib versus placebo in patients with advanced pancreatic NET whose disease has progressed after prior therapy. VI. To evaluate the overall radiographic response rate of cabozantinib versus placebo in patients with advanced carcinoid tumors whose disease has progressed after prior therapy. OTHER OBJECTIVE: I. Results of the primary analysis will be examined for consistency, while taking into account the stratification factors and/or covariates of baseline quality of life (QOL) and fatigue. QUALITY OF LIFE SUBSTUDY OBJECTIVE: I. To compare overall quality of life, disease-related symptoms, and other domains between the two treatment groups (cabozantinib versus [vs.] placebo) within each cohort of patients (pancreatic NET vs. carcinoid tumor). (Quality of Life Substudy Objective - A021602-HO1) POPULATION PHARMACOKINETICS SUBSTUDY OBJECTIVE: I. To describe the population pharmacokinetic and exposure-response relationships of cabozantinib in patients with advanced neuroendocrine tumors. (Population Pharmacokinetics Substudy Objective - A021602-PP1) OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive cabozantinib S-malate orally (PO) once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood and urine sample collection, and computed tomography (CT), magnetic resonance imaging (MRI), and/or x-ray imaging during screening and on study. ARM II: Patients receive placebo PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood and urine sample collection, and CT, MRI, and/or x-ray imaging during screening and on study. Patients may crossover to receive cabozantinib S-malate at the time of disease progression. After completion of study treatment, patients are followed up every 12 weeks until disease progression or start of new anticancer therapy, and then every 6 months until 8 years after registration.

Carcinoid Tumor
Functioning Pancreatic Neuroendocrine Tumor
Intermediate Grade Lung Neuroendocrine Neoplasm
Locally Advanced Digestive System Neuroendocrine Neoplasm
Locally Advanced Digestive System Neuroendocrine Tumor G1
Locally Advanced Lung Neuroendocrine Neoplasm
Locally Advanced Pancreatic Neuroendocrine Tumor
Locally Advanced Unresectable Digestive System Neuroendocrine Neoplasm
Low Grade Lung Neuroendocrine Neoplasm
Lung Neuroendocrine Tumor
Lung Neuroendocrine Tumor G2
Metastatic Digestive System Neuroendocrine Neoplasm
Metastatic Digestive System Neuroendocrine Tumor G1
Metastatic Lung Neuroendocrine Neoplasm
Metastatic Lung Neuroendocrine Tumor
Metastatic Pancreatic Neuroendocrine Neoplasm
Metastatic Pancreatic Neuroendocrine Tumor
Metastatic Thymus Neuroendocrine Neoplasm
Neuroendocrine Neoplasm
Neuroendocrine Tumor G2
Non-Functioning Pancreatic Neuroendocrine Tumor
Pancreatic Serotonin-Producing Neuroendocrine Tumor
Thymus Neuroendocrine Tumor
Unresectable Digestive System Neuroendocrine Neoplasm
Unresectable Digestive System Neuroendocrine Tumor G1
Unresectable Lung Neuroendocrine Neoplasm
Unresectable Pancreatic Neuroendocrine Neoplasm
Unresectable Thymus Neuroendocrine Neoplasm

PROCEDURE: Biospecimen Collection
DRUG: Cabozantinib S-malate
PROCEDURE: Computed Tomography
PROCEDURE: Magnetic Resonance Imaging
OTHER: Placebo Administration
OTHER: Quality-of-Life Assessment
PROCEDURE: X-Ray Imaging

NCI-2017-02297
NCI-2017-02297 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
A021602 (OTHER Identifier) (OTHER: Alliance for Clinical Trials in Oncology)
A021602 (OTHER Identifier) (OTHER: CTEP)
U10CA180821 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2017-12-15	Results First Submitted 2024-08-20	Last Update Submitted that met QC Criteria 2025-03-19
First Submitted that Met QC Criteria 2017-12-15	Results First Submitted that Met QC Criteria 2024-09-25	Last Update Posted (ACTUAL) 2025-03-20
First Posted (ACTUAL) 2017-12-18	Results First Posted 2024-10-16	Last Verified 2024-12

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Randomized

Interventional Model:
Parallel

Masking:
Double

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Arm I (cabozantinib S-malate) Patients receive cabozantinib S-malate PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood and urine sample collection, and CT, MRI, and/or x-ray imaging	PROCEDURE: Biospecimen Collection Undergo blood and urine sample collection DRUG: Cabozantinib S-malate Given PO PROCEDURE: Computed Tomography Undergo CT PROCEDURE: Magnetic Resonance Imaging Undergo MRI OTHER: Quality-of-Life Assessment Ancillary studies PROCEDURE: X-Ray Imaging Undergo x-ray
PLACEBO_COMPARATOR: Arm II (placebo) Patients receive placebo PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood and urine sample collection, and CT, MRI, and/or x-ray imaging during screen	PROCEDURE: Biospecimen Collection Undergo blood and urine sample collection PROCEDURE: Computed Tomography Undergo CT PROCEDURE: Magnetic Resonance Imaging Undergo MRI OTHER: Placebo Administration Given PO OTHER: Quality-of-Life Assessment Ancillary studies PROCEDURE: X-Ray Imaging Undergo x-ray

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Arm I (cabozantinib S-malate)

Patients receive cabozantinib S-malate PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood and urine sample collection, and CT, MRI, and/or x-ray imaging

PROCEDURE: Biospecimen Collection

Undergo blood and urine sample collection

DRUG: Cabozantinib S-malate

Given PO

PROCEDURE: Computed Tomography

Undergo CT

PROCEDURE: Magnetic Resonance Imaging

Undergo MRI

OTHER: Quality-of-Life Assessment

Ancillary studies

PROCEDURE: X-Ray Imaging

Undergo x-ray

PLACEBO_COMPARATOR: Arm II (placebo)

Patients receive placebo PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood and urine sample collection, and CT, MRI, and/or x-ray imaging during screen

PROCEDURE: Biospecimen Collection

Undergo blood and urine sample collection

PROCEDURE: Computed Tomography

Undergo CT

PROCEDURE: Magnetic Resonance Imaging

Undergo MRI

OTHER: Placebo Administration

Given PO

OTHER: Quality-of-Life Assessment

Ancillary studies

PROCEDURE: X-Ray Imaging

Undergo x-ray

Primary Outcome Measures	Measure Description	Time Frame
Progression-free Survival (PFS)	Will be assessed per Response Evaluation Criteria in Solid Tumors 1.1 determined by retrospective independent central review. Will be compared between treatment arms using the stratified log rank test at one-sided level 0.025. The stratification factors will be used for the analysis. The hazard ratio (HR) for PFS will be estimated using a stratified Cox proportional hazards model, and the 95% confidence interval (CI) for the HR will be provided. Results from an unstratified analysis will also be provided. Kaplan-Meier methodology will be used to estimate the median PFS for each treatment arm, and Kaplan-Meier curves will be produced. Brookmeyer Crowley methodology will be used to construct the 95% CI for the median PFS for each treatment arm.	36 months

Secondary Outcome Measures	Measure Description	Time Frame
Overall Survival (OS)	The analyses for OS will follow intent-to-treat (ITT) principle and will be conducted separately within each cohort (pancreatic neuroendocrine tumor [NET] and carcinoid tumor). The distribution of OS will be estimated using the method of Kaplan-Meier. The median OS, along with the 95% CI, will be estimated by the two treatment groups. Overall survival will be compared between treatment arms using the stratified log-rank test at a one-sided cumulative 2.5% level of significance. The stratified Cox regression will be used to estimate the HR of OS, along with the 95% CI. A hierarchical approach will be used to control for family-wise type-I error rate, therefore OS will be formally statistically tested only if the primary efficacy endpoint, PFS, is statistically significantly different between the two treatment groups.	60 months
Number of Patients Experiencing Grade 3+ Adverse Events (AEs) Graded According to the Common Terminology Criteria for Adverse Events (CTCAE) and Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)	For CTCAE data, the frequency tables will be reviewed to determine the patterns. The overall adverse event rates will be compared between treatment groups using Chi-square test (or Fisher's exact test if the data in contingency table is sparse). PRO-CTCAE data will, at minimum, be analyzed similarly to CTCAE data. The initial analysis of each PRO-CTCAE item will use all available scores in an analysis which mirrors the approach used for the CTCAE data. Supplemental analysis will use model-based multiple imputation incorporating baseline patient characteristics and physician-rated performance status. CTCAE data may be incorporated as auxiliary data into multiple imputation models for AEs which are captured by both PRO-CTCAE and CTCAE. Results from supplemental analysis will be descriptively compared to the results of the initial analysis to assess the robustness of results to missing data. Additional analyses of PRO-CTCAE data beyond those specified above may be undertaken.	60 months
Radiographic Response Rate	Will be defined as the proportion of patients in each arm whose best response is either complete response (CR) or partial response (PR). Radiographic response rate for both cohorts: the analyses for confirmed radiographic response rate will follow the ITT principle and will be conducted separately within each cohort (pancreatic NET and carcinoid tumor). The proportion of patients with either confirmed CR or confirmed PR as their best response will be estimated using point estimates and 95% confidence intervals. Radiographic response rate will be compared between treatment arms using the 2-sample z-test to compare sample proportion at a one-sided 2.5% level of significance.	36 months

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Documentation of Disease:

Histologic Documentation: Well- or moderately-differentiated neuroendocrine tumors of pancreatic and non-pancreatic (i.e. carcinoid) origin by local pathology

The pathology report must state ONE of the following: 1) well- or moderately-differentiated neuroendocrine tumor, 2) low- or intermediate-grade neuroendocrine tumor, or 3) carcinoid tumor or atypical carcinoid tumor; documentation of histology from a primary or metastatic site is allowed
Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma without specification of differentiation status, adenocarcinoid tumor, or goblet cell carcinoid tumor are not eligible. Patients with well-differentiated grade 3 neuroendocrine tumor are eligible
Stage: Locally advanced/unresectable or metastatic disease
Tumor Site: Histological documentation of neuroendocrine tumor of pancreatic, gastrointestinal (GI), lung, thymus, other, or unknown primary site; GI, lung, thymus, other, and unknown primary NETs will enroll in the carcinoid tumor cohort of the study

Functional (i.e., associated with symptoms or clinical syndrome related to hormone secretion by tumor) or nonfunctional tumors are allowed
Radiologic Evaluation: Target lesions must have shown evidence of disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria in the 12 months prior to registration; the radiologic images, imaging reports, and clinic notes indicating growth of existing lesions, development of new lesions, or treatment changes must be submitted
Measurable Disease

Patients must have measurable disease per RECIST 1.1 by computer tomography (CT) scan or magnetic resonance imaging (MRI)
Lesions must be accurately measured in at least one dimension (longest diameter to be recorded) as >= 1 cm with CT or MRI (or >= 1.5 cm for lymph nodes); non-measurable disease includes disease smaller than these dimensions or lesions considered truly non-measurable including: leptomeningeal disease, ascites, pleural or pericardial effusion, lymphangitic involvement of skin or lung
Prior Treatment

Patient must have experienced disease progression after receiving or intolerance leading to treatment discontinuation of at least one Food and Drug Administration (FDA)-approved line of therapy (except somatostatin analogs); prior lines of therapy must include one of the following: everolimus, sunitinib, or lutetium Lu 177 dotatate in patients with pancreatic NET; everolimus in patients with lung NET; everolimus or lutetium Lu 177 dotatate in patients with gastrointestinal NET
Prior treatment (except somatostatin analogs) with biologic therapy, immunotherapy, chemotherapy, investigational agent for malignancy, and/or radiation must be completed at least 28 days prior to registration
Prior treatment with somatostatin analogs is allowed, and continuation of treatment with somatostatin analogs while on cabozantinib/placebo is allowed provided that the patient has been on a stable dose for at least two months
Prior systemic treatment with radionuclide therapy must be completed at least 6 weeks prior to registration
Prior treatment with hepatic artery embolization (including bland embolization, chemoembolization, and selective internal radiation therapy) or ablative therapies is allowed if measurable disease remains outside of the treated area or if there is documented disease progression in a treated site; prior liver-directed or other ablative treatment must be completed at least 28 days prior to registration
Prior treatment with cabozantinib is not allowed
Patients should have resolution of any toxic effects of prior therapy (except alopecia and fatigue) to National Cancer Institute (NCI) CTCAE, version 5.0, grade 1 or less
Patients must have completed any major surgery at least 12 weeks prior to registration and any minor surgery (including uncomplicated tooth extractions) at least 28 days prior to registration; complete wound healing from major surgery must have occurred at least 28 days prior to registration, and complete wound healing from minor surgery must have occurred at least 10 days prior to registration
Patient History

No class III or IV congestive heart failure (CHF) within 6 months of registration
No clinically significant cardiac arrhythmia within 6 months of registration
No unstable angina or myocardial infarction (MI) within 6 months of registration
No thromboembolic events within 6 months of registration (including [incl.] stroke, transient ischemic attack [TIA], deep vein thrombosis [DVT], & pulmonary embolism [PE])
No known history of congenital long QT syndrome
No uncontrolled hypertension within 14 days of registration (defined as systolic blood pressure [SBP] >= 150 mmHg and/or diastolic blood pressure [DBP] >= 90 mmHg despite optimal medical management)
No clinically significant GI bleeding within 6 months of registration
No clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding within 6 months of registration including, but not limited to: active peptic ulcer, known endoluminal metastatic lesion(s) with history of bleeding, inflammatory bowel disease, or other gastrointestinal conditions with increased risk of perforation
No GI perforation within 6 months of registration
No known tumor with invasion into the GI tract from the outside causing increased risk of perforation or bleeding within 28 days of registration
No radiologic or clinical evidence of pancreatitis
No known cavitary lung lesions
No known endobronchial lesions involving the main or lobar bronchi and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage; (CT with contrast is recommended to evaluate such lesions)
No hemoptysis greater than 1/2 teaspoon (2.5 mL) or any other signs of pulmonary hemorrhage within the 3 months prior to registration
No known tumor invading or encasing any major blood vessels
No history of non-healing wounds or ulcers within 28 days of registration
No history of fracture within 28 days of registration
No brain metastases or cranial epidural disease unless adequately treated, stable, and off steroid support for at least 4 weeks prior to registration
No known medical condition causing an inability to swallow oral formulations of agents
No history of allergic reaction attributed to compounds of similar chemical or biological composition to cabozantinib/placebo
No "currently active" second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ; patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for >= 3 years
Concomitant Medications

Other planned concurrent investigational agents or other tumor directed therapies (chemotherapy, radiation) are not allowed while on this study
Concurrent use of somatostatin analogs while on cabozantinib/placebo is allowed provided that the patient has been on a stable dose for at least two months
Full dose oral anticoagulation/antiplatelet therapy is not permitted; low dose aspirin =< 81 mg/day is allowed; anticoagulation with therapeutic doses of low molecular weight heparin (LMWH) is allowed in patients who are on a stable dose of LMWH for at least 6 weeks prior to registration; treatment with warfarin is not allowed; anticoagulation in patients with brain metastases is not permitted
Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed; patients must discontinue the drug at least 14 days prior to registration on the study
Chronic concomitant treatment with strong CYP3A4 inducers is not allowed; patients must discontinue the drug at least 14 days prior to registration on the study
Not pregnant and not nursing

Women of childbearing potential must have a negative pregnancy test done =< 14 days prior to registration
A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months)
Age >= 18 years
Eastern Cooperative Oncology Group (ECOG) performance status: 0-2
Absolute neutrophil count (ANC) >= 1,500/mm^3
Hemoglobin >= 9 g/dL
Platelet count >= 100,000/mm^3
Prothrombin time (PT)/ international normalized ratio (INR), partial thromboplastin time (PTT) < 1.3 x upper limit of normal (ULN)
Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) =< 3 x ULN
Total bilirubin =< 1.5 x ULN

Except in the case of Gilbert disease, in which case total bilirubin must be =< 3 x ULN
Creatinine =< 1.5 mg/dL OR creatinine clearance >= 45 mL/min
Albumin >= 2.8 g/dL
Potassium within normal limits (WNL)

Supplementation is acceptable to achieve a value WNL; in patients with low albumin levels, a corrected calcium value WNL is acceptable; in patients with abnormal thyroid stimulating hormone (TSH), if free T4 is normal and patient is clinically euthyroid, patient is eligible
Phosphorus WNL

Supplementation is acceptable to achieve a value WNL; in patients with low albumin levels, a corrected calcium value WNL is acceptable; in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible
Calcium WNL

Supplementation is acceptable to achieve a value WNL; in patients with low albumin levels, a corrected calcium value WNL is acceptable; in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible
Magnesium WNL

Supplementation is acceptable to achieve a value WNL; in patients with low albumin levels, a corrected calcium value WNL is acceptable; in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible
Urine protein to creatinine (UPC) ratio =< 1
QT interval corrected for heart rate using Fridericia's formula (QTcF) =< 500 msec
TSH WNL

Supplementation is acceptable to achieve a value WNL; in patients with low albumin levels, a corrected calcium value WNL is acceptable; in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

PRINCIPAL_INVESTIGATOR: Jennifer A Chan, Alliance for Clinical Trials in Oncology

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Kunz PL. Angiogenesis inhibitors in neuroendocrine tumours: finally coming of age. Lancet Oncol. 2020 Nov;21(11):1395-1397. doi: 10.1016/S1470-2045(20)30560-X. No abstract available.

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