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Active, not recruitingNCT03375320Updated Sep 22, 2026Results posted

Testing Cabozantinib in Patients With Advanced Pancreatic Neuroendocrine and Carcinoid Tumors

A Phase 3 interventional study of Biospecimen Collection and Cabozantinib S-malate in Functioning Pancreatic Neuroendocrine Tumor, Intermediate Grade Lung Neuroendocrine Neoplasm and Locally Advanced Digestive System Neuroendocrine Neoplasm, sponsored by National Cancer Institute (NCI). Active, not recruiting at 432 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-09-22.

Sponsored by National Cancer Institute (NCI) · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
298
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study summary

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.

Read the detailed description

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.

02

Conditions studied

  • 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
  • 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
03

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility criteria

Inclusion Criteria:

  • 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
04

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Participant, Investigator)
Enrollment
298 participants (actual)

Study arms

  • 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 during screening and on study.

    Procedure: Biospecimen Collection · Drug: Cabozantinib S-malate · Procedure: Computed Tomography · Procedure: Magnetic Resonance Imaging · Other: Quality-of-Life Assessment · Procedure: X-Ray Imaging

  • 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 screening and on study. Patients may crossover to receive cabozantinib S-malate at the time of disease progression.

    Procedure: Biospecimen Collection · Procedure: Computed Tomography · Procedure: Magnetic Resonance Imaging · Other: Placebo Administration · Other: Quality-of-Life Assessment · Procedure: X-Ray Imaging

Interventions

  • ProcedureBiospecimen Collection

    Undergo blood and urine sample collection

    Also known as: Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection

  • DrugCabozantinib S-malate

    Given PO

    Also known as: BMS-907351, Cabometyx, Cometriq, XL 184, XL-184, XL184

  • ProcedureComputed Tomography

    Undergo CT

    Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

  • ProcedureMagnetic Resonance Imaging

    Undergo MRI

    Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

  • OtherPlacebo Administration

    Given PO

  • OtherQuality-of-Life Assessment

    Ancillary studies

    Also known as: Quality of Life Assessment

  • ProcedureX-Ray Imaging

    Undergo x-ray

    Also known as: Conventional X-Ray, Diagnostic Radiology, Medical Imaging, X-Ray, Plain film radiographs, Radiographic Imaging, Radiographic imaging procedure (procedure), Radiography, RG, Static X-Ray, X-Ray

05

What researchers measure

Primary outcomes

  1. 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.

    Time frame: 36 months

Secondary outcomes

  1. 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.

    Time frame: 60 months

  2. 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.

    Time frame: 60 months

  3. 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.

    Time frame: 36 months

06

Results

Posted Oct 16, 2024

Participant flow

Participant flow — Overall Study
MilestoneArm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])Arm IIb (Placebo, Pancreatic NET Cohort [pNET])
Started134696431
Initiated treatment132676331
Completed217142
Not completed113625029
Withdrew: Adverse event349100
Withdrew: Death6300
Withdrew: Withdrawal by subject7454
Withdrew: Progressive disease55412924
Withdrew: Alternative treatment6110
Withdrew: Other disease1130
Withdrew: Withdrawal prior to initiation2210
Withdrew: Physician decision1111
Withdrew: Non-compliance1000

Outcome measures

PrimaryProgression-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.

Time frame:
36 months
Reported as:
Median · months
Progression-free Survival (PFS)
monthsArm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])Arm IIb (Placebo, Pancreatic NET Cohort [pNET])
Progression-free Survival (PFS)8.4 (7.6 to 12.7)3.9 (3.0 to 5.7)13.8 (9.2 to 18.5)4.4 (3.0 to 5.9)
Statistical analysis
  • Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET]) vs Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET]) · One-sided unstratified log-rank · p = <0.0001
  • Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET]) vs Arm IIb (Placebo, Pancreatic NET Cohort [pNET]) · One-sided unstratified log-rank · p = <0.0001
SecondaryOverall 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.

Time frame:
60 months
Reported as:
Median · months
Overall Survival (OS)
monthsArm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])Arm IIb (Placebo, Pancreatic NET Cohort [pNET])
Overall Survival (OS)21.9 (18.8 to 30.4)19.7 (14.2 to 30.0)40.0 (31.3 to NA)31.1 (23.4 to NA)
Statistical analysis
  • Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET]) vs Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET]) · One-sided stratified log-rank · p = 0.2438
  • Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET]) vs Arm IIb (Placebo, Pancreatic NET Cohort [pNET]) · One-sided stratified log-rank · p = 0.4426
SecondaryNumber 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.

Time frame:
60 months
Reported as:
Count of participants · Participants
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)
ParticipantsArm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])Arm IIb (Placebo, Pancreatic NET Cohort [pNET])
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)104474922
SecondaryRadiographic 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.

Time frame:
36 months
Reported as:
Count of participants · Participants
Radiographic Response Rate
ParticipantsArm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])Arm IIb (Placebo, Pancreatic NET Cohort [pNET])
Radiographic Response Rate70120
Statistical analysis
  • Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET]) vs Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET]) · Chi-squared · p = 0.05
  • Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET]) vs Arm IIb (Placebo, Pancreatic NET Cohort [pNET]) · Chi-squared · p = 0.01

Adverse events

Collected over 60 months. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])60/134 (44.8%)89/134 (66.4%)134/134 (100%)
Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])37/69 (53.6%)41/69 (59.4%)69/69 (100%)
Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])21/64 (32.8%)49/64 (76.6%)64/64 (100%)
Arm IIb (Placebo, Pancreatic NET Cohort [pNET])11/31 (35.5%)21/31 (67.7%)31/31 (100%)
Most frequent serious events
Showing 10 of 151
Most frequent serious events
EventArm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])Arm IIb (Placebo, Pancreatic NET Cohort [pNET])
HypertensionVascular disorders30/1345/6916/648/31
FatigueGeneral disorders15/1347/6910/644/31
Abdominal painGastrointestinal disorders9/1345/694/644/31
Thromboembolic eventVascular disorders2/1342/698/640/31
DiarrheaGastrointestinal disorders15/1345/694/640/31
Lymphocyte count decreasedInvestigations13/1341/692/640/31
HyperglycemiaMetabolism and nutrition disorders0/1342/695/643/31
Small intestinal obstructionGastrointestinal disorders2/1341/691/643/31
Mucositis oralGastrointestinal disorders4/1341/695/640/31
NauseaGastrointestinal disorders3/1341/695/642/31
Most frequent other events
Showing 10 of 284
Most frequent other events
EventArm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])Arm IIb (Placebo, Pancreatic NET Cohort [pNET])
Aspartate aminotransferase increasedInvestigations96/13417/6950/6415/31
FatigueGeneral disorders103/13442/6948/6417/31
Alanine aminotransferase increasedInvestigations89/13415/6949/6412/31
DiarrheaGastrointestinal disorders82/13431/6940/6410/31
Platelet count decreasedInvestigations74/1348/6924/646/31
HypertensionVascular disorders65/13427/6931/6411/31
HyperglycemiaMetabolism and nutrition disorders50/13425/6926/6415/31
Mucositis oralGastrointestinal disorders48/1346/6926/642/31
NauseaGastrointestinal disorders53/13413/6921/648/31
Palmar-plantar erythrodysesthesia syndrmSkin and subcutaneous tissue disorders47/1345/6924/645/31

Baseline characteristics

Age, Continuous
Age, Continuous(years)Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])Arm IIb (Placebo, Pancreatic NET Cohort [pNET])Total
Median66 (28 to 86)66 (30 to 82)59.5 (29 to 79)64 (39 to 79)66 (28 to 86)
Sex: Female, Male
Sex: Female, Male(Participants)Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])Arm IIb (Placebo, Pancreatic NET Cohort [pNET])Total
Female74312713145
Male60383718153
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])Arm IIb (Placebo, Pancreatic NET Cohort [pNET])Total
Hispanic or Latino892221
Not Hispanic or Latino125566126268
Unknown or Not Reported14139
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])Arm IIb (Placebo, Pancreatic NET Cohort [pNET])Total
American Indian or Alaska Native00101
Asian31408
Native Hawaiian or Other Pacific Islander00101
Black or African American973322
White115555425249
More than one race00101
Unknown or Not Reported760316
Region of Enrollment
Region of Enrollment(participants)Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])Arm IIb (Placebo, Pancreatic NET Cohort [pNET])Total
United States134696431298
07

Study locations

432 sites
  • Katmai Oncology Group
    Anchorage, Alaska 99508, United States
  • Kingman Regional Medical Center
    Kingman, Arizona 86401, United States
  • Mayo Clinic Hospital in Arizona
    Phoenix, Arizona 85054, United States
  • Banner University Medical Center - Tucson
    Tucson, Arizona 85719, United States
  • University of Arizona Cancer Center-North Campus
    Tucson, Arizona 85719, United States
  • University of Arkansas for Medical Sciences
    Little Rock, Arkansas 72205, United States
  • Kaiser Permanente-Deer Valley Medical Center
    Antioch, California 94531, United States
  • PCR Oncology
    Arroyo Grande, California 93420, United States
  • Sutter Auburn Faith Hospital
    Auburn, California 95602, United States
  • Alta Bates Summit Medical Center-Herrick Campus
    Berkeley, California 94704, United States
  • Mills-Peninsula Medical Center
    Burlingame, California 94010, United States
  • City of Hope Comprehensive Cancer Center
    Duarte, California 91010, United States
  • Epic Care-Dublin
    Dublin, California 94568, United States
  • Epic Care Partners in Cancer Care
    Emeryville, California 94608, United States
  • Kaiser Permanente-Fremont
    Fremont, California 94538, United States
  • Palo Alto Medical Foundation-Fremont
    Fremont, California 94538, United States
  • Kaiser Permanente-Fresno
    Fresno, California 93720, United States
  • Contra Costa Regional Medical Center
    Martinez, California 94553-3156, United States
  • Fremont - Rideout Cancer Center
    Marysville, California 95901, United States
  • Memorial Medical Center
    Modesto, California 95355, United States
  • Kaiser Permanente-Modesto
    Modesto, California 95356, United States
  • Palo Alto Medical Foundation-Camino Division
    Mountain View, California 94040, United States
  • Alta Bates Summit Medical Center - Summit Campus
    Oakland, California 94609, United States
  • Kaiser Permanente-Oakland
    Oakland, California 94611, United States
  • Palo Alto Medical Foundation Health Care
    Palo Alto, California 94301, United States
  • Stanford Cancer Institute Palo Alto
    Palo Alto, California 94304, United States
  • Kaiser Permanente-Redwood City
    Redwood City, California 94063, United States
  • Kaiser Permanente-Richmond
    Richmond, California 94801, United States
  • Kaiser Permanente-Roseville
    Roseville, California 95661, United States
  • Sutter Roseville Medical Center
    Roseville, California 95661, United States
  • Kaiser Permanente Downtown Commons
    Sacramento, California 95814, United States
  • Sutter Medical Center Sacramento
    Sacramento, California 95816, United States
  • University of California Davis Comprehensive Cancer Center
    Sacramento, California 95817, United States
  • Kaiser Permanente-South Sacramento
    Sacramento, California 95823, United States
  • Salinas Valley Memorial
    Salinas, California 93901, United States
  • California Pacific Medical Center-Pacific Campus
    San Francisco, California 94115, United States
  • Kaiser Permanente-San Francisco
    San Francisco, California 94115, United States
  • UCSF Medical Center-Mission Bay
    San Francisco, California 94158, United States
  • Kaiser Permanente-Santa Teresa-San Jose
    San Jose, California 95119, United States
  • Kaiser Permanente San Leandro
    San Leandro, California 94577, United States
  • Mills Health Center
    San Mateo, California 94401, United States
  • Kaiser Permanente-San Rafael
    San Rafael, California 94903, United States
  • Kaiser San Rafael-Gallinas
    San Rafael, California 94903, United States
  • Kaiser Permanente Medical Center - Santa Clara
    Santa Clara, California 95051, United States
  • Palo Alto Medical Foundation-Santa Cruz
    Santa Cruz, California 95065, United States
  • Kaiser Permanente-Santa Rosa
    Santa Rosa, California 95403, United States
  • Kaiser Permanente-South San Francisco
    South San Francisco, California 94080, United States
  • Kaiser Permanente-Stockton
    Stockton, California 95210, United States
  • Palo Alto Medical Foundation-Sunnyvale
    Sunnyvale, California 94086, United States
  • Kaiser Permanente Medical Center-Vacaville
    Vacaville, California 95688, United States
  • Kaiser Permanente-Vallejo
    Vallejo, California 94589, United States
  • Sutter Solano Medical Center/Cancer Center
    Vallejo, California 94589, United States
  • Kaiser Permanente-Walnut Creek
    Walnut Creek, California 94596, United States
  • Rocky Mountain Cancer Centers-Aurora
    Aurora, Colorado 80012, United States
  • Rocky Mountain Cancer Centers-Boulder
    Boulder, Colorado 80304, United States
  • Penrose-Saint Francis Healthcare
    Colorado Springs, Colorado 80907, United States
  • National Jewish Health-Main Campus
    Denver, Colorado 80206, United States
  • Rocky Mountain Cancer Centers-Midtown
    Denver, Colorado 80218, United States
  • Saint Joseph Hospital - Cancer Centers of Colorado
    Denver, Colorado 80218, United States
  • Rocky Mountain Cancer Centers-Rose
    Denver, Colorado 80220, United States
  • Mountain Blue Cancer Care Center - Swedish
    Englewood, Colorado 80113, United States
  • Swedish Medical Center
    Englewood, Colorado 80113, United States
  • National Jewish Health-Western Hematology Oncology
    Golden, Colorado 80401, United States
  • Saint Mary's Hospital and Regional Medical Center
    Grand Junction, Colorado 81501, United States
  • Banner North Colorado Medical Center
    Greeley, Colorado 80631, United States
  • Good Samaritan Hospital - Cancer Centers of Colorado
    Lafayette, Colorado 80026, United States
  • Rocky Mountain Cancer Centers-Littleton
    Littleton, Colorado 80120, United States
  • Rocky Mountain Cancer Centers-Sky Ridge
    Lone Tree, Colorado 80124, United States
  • Banner North Colorado Medical Center - Loveland Campus
    Loveland, Colorado 80539, United States
  • National Jewish Health-Northern Hematology Oncology
    Thornton, Colorado 80260, United States
  • Intermountain Health Lutheran Hospital
    Wheat Ridge, Colorado 80401, United States
  • Danbury Hospital
    Danbury, Connecticut 06810, United States
  • Norwalk Hospital
    Norwalk, Connecticut 06856, United States
  • MedStar Georgetown University Hospital
    Washington D.C., District of Columbia 20007, United States
  • GenesisCare USA - Aventura FP
    Aventura, Florida 33180, United States
  • GenesisCare USA - Aventura
    Aventura, Florida 33180, United States
  • GenesisCare USA - Boca Ration FP06
    Boca Raton, Florida 33431, United States
  • Regional Cancer Center-Lee Memorial Health System
    Fort Myers, Florida 33905, United States
  • Memorial Regional Hospital/Joe DiMaggio Children's Hospital
    Hollywood, Florida 33021, United States
  • Mayo Clinic in Florida
    Jacksonville, Florida 32224-9980, United States
  • Moffitt Cancer Center
    Tampa, Florida 33612, United States
  • Emory University Hospital Midtown
    Atlanta, Georgia 30308, United States
  • Emory University Hospital/Winship Cancer Institute
    Atlanta, Georgia 30322, United States
  • Emory Saint Joseph's Hospital
    Atlanta, Georgia 30342, United States
  • Hawaii Cancer Care Inc - Waterfront Plaza
    Honolulu, Hawaii 96813, United States
  • Queen's Cancer Cenrer - POB I
    Honolulu, Hawaii 96813, United States
  • Queen's Medical Center
    Honolulu, Hawaii 96813, United States
  • Straub Clinic and Hospital
    Honolulu, Hawaii 96813, United States
  • Queen's Cancer Center - Kuakini
    Honolulu, Hawaii 96817, United States
  • Kaiser Permanente Moanalua Medical Center
    Honolulu, Hawaii 96819, United States
  • Hawaii Cancer Care - Westridge
    ‘Aiea, Hawaii 96701, United States
  • Pali Momi Medical Center
    ‘Aiea, Hawaii 96701, United States
  • Saint Alphonsus Cancer Care Center-Boise
    Boise, Idaho 83706, United States
  • Saint Luke's Cancer Institute - Boise
    Boise, Idaho 83712, United States
  • Saint Alphonsus Cancer Care Center-Caldwell
    Caldwell, Idaho 83605, United States
  • Kootenai Health - Coeur d'Alene
    Coeur d'Alene, Idaho 83814, United States
  • Walter Knox Memorial Hospital
    Emmett, Idaho 83617, United States
  • Saint Luke's Cancer Institute - Fruitland
    Fruitland, Idaho 83619, United States
  • Idaho Urologic Institute-Meridian
    Meridian, Idaho 83642, United States
  • Saint Luke's Cancer Institute - Meridian
    Meridian, Idaho 83642, United States

Showing the first 100 of 432 sites.

08

References and documents

Publications

  • Strosberg JR, Zemla T, Geyer S, Pulsipher S, Ou FS, Behr S, Raj N, Vijayvergia N, Dasari A, O'Reilly EM, Meyerhardt JA, Wolin EM, Halfdanarson TR, Chan JA. Cabozantinib for advanced grade 3 neuroendocrine tumors: subgroup analysis of the phase 3 CABINET trial (Alliance A021602). Endocr Relat Cancer. 2026 Jan 24;33(1):e250415. doi: 10.1530/ERC-25-0415. Print 2026 Jan 1. PubMed 41524552 ↗
  • Chan JA, Geyer S, Zemla T, Knopp MV, Behr S, Pulsipher S, Ou FS, Dueck AC, Acoba J, Shergill A, Wolin EM, Halfdanarson TR, Konda B, Trikalinos NA, Tawfik B, Raj N, Shaheen S, Vijayvergia N, Dasari A, Strosberg JR, Kohn EC, Kulke MH, O'Reilly EM, Meyerhardt JA. Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors. N Engl J Med. 2025 Feb 13;392(7):653-665. doi: 10.1056/NEJMoa2403991. Epub 2024 Sep 16. PubMed 39282913 ↗
  • 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. PubMed 33152282 ↗

Study documents

  • Protocol and statistical analysis plan · Dec 7, 2022

Documents are hosted by the registry — open the source record to download them.

09

Registry details

Key details

Study ID
NCT03375320
Lead sponsor
National Cancer Institute (NCI)
Responsible party
Sponsor
First posted
Dec 18, 2017
Start date
Oct 26, 2018
Primary completion
Aug 23, 2023
Completion
Sep 1, 2027 (estimated)
Results posted
Oct 16, 2024
Last update
Sep 22, 2026

Study contacts

Jennifer A Chan
principal investigator · Alliance for Clinical Trials in Oncology

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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