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Testing Cabozantinib in Patients With Advanced Pancreatic Neuroendocrine and Carcinoid Tumors

Randomized, Double-Blinded Phase III Study of CABozantinib Versus Placebo IN Patients With Advanced NEuroendocrine Tumors After Progression on Prior Therapy (CABINET)

Status
Active, not recruiting
Phases
Phase 3
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT03375320
Enrollment
298
Registered
2017-12-18
Start date
2018-10-26
Completion date
2026-08-19
Last updated
2026-08-04

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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

Brief 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.

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.

Interventions

PROCEDUREBiospecimen Collection

Undergo blood and urine sample collection

DRUGCabozantinib S-malate

Given PO

PROCEDUREComputed Tomography

Undergo CT

PROCEDUREMagnetic Resonance Imaging

Undergo MRI

OTHERPlacebo Administration

Given PO

OTHERQuality-of-Life Assessment

Ancillary studies

PROCEDUREX-Ray Imaging

Undergo x-ray

Sponsors

National Cancer Institute (NCI)
Lead SponsorNIH

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No

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

Design outcomes

Primary

MeasureTime frameDescription
Progression-free Survival (PFS)36 monthsWill 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.

Secondary

MeasureTime frameDescription
Overall Survival (OS)60 monthsThe 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.
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)60 monthsFor 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.
Radiographic Response Rate36 monthsWill 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.

Countries

United States

Contacts

PRINCIPAL_INVESTIGATORJennifer A Chan

Alliance for Clinical Trials in Oncology

Participant flow

Participants by arm

ArmCount
Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])
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 CT, MRI, and/or x-ray imaging during screening and on study.\> \> Cabozantinib S-malate: Given PO\> \> Computed Tomography: Undergo CT\> \> Magnetic Resonance Imaging: Undergo MRI\> \> Quality-of-Life Assessment: Ancillary studies\> \> X-Ray Imaging: Undergo x-ray
134
Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])
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 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.\> \> Computed Tomography: Undergo CT\> \> Magnetic Resonance Imaging: Undergo MRI\> \> Placebo Administration: Given PO\> \> Quality-of-Life Assessment: Ancillary studies\> \> X-Ray Imaging: Undergo x-ray
69
Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])
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 CT, MRI, and/or x-ray imaging during screening and on study.\> \> Cabozantinib S-malate: Given PO\> \> Computed Tomography: Undergo CT\> \> Magnetic Resonance Imaging: Undergo MRI\> \> Quality-of-Life Assessment: Ancillary studies\> \> X-Ray Imaging: Undergo x-ray
64
Arm IIb (Placebo, Pancreatic NET Cohort [pNET])
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 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.\> \> Computed Tomography: Undergo CT\> \> Magnetic Resonance Imaging: Undergo MRI\> \> Placebo Administration: Given PO\> \> Quality-of-Life Assessment: Ancillary studies\> \> X-Ray Imaging: Undergo x-ray
31
Total298

Baseline characteristics

CharacteristicArm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])TotalArm IIb (Placebo, Pancreatic NET Cohort [pNET])Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])
Age, Continuous66 years66 years64 years59.5 years66 years
Ethnicity (NIH/OMB)
Hispanic or Latino
8 Participants21 Participants2 Participants2 Participants9 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
125 Participants268 Participants26 Participants61 Participants56 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
1 Participants9 Participants3 Participants1 Participants4 Participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants1 Participants0 Participants1 Participants0 Participants
Race (NIH/OMB)
Asian
3 Participants8 Participants0 Participants4 Participants1 Participants
Race (NIH/OMB)
Black or African American
9 Participants22 Participants3 Participants3 Participants7 Participants
Race (NIH/OMB)
More than one race
0 Participants1 Participants0 Participants1 Participants0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants1 Participants0 Participants1 Participants0 Participants
Race (NIH/OMB)
Unknown or Not Reported
7 Participants16 Participants3 Participants0 Participants6 Participants
Race (NIH/OMB)
White
115 Participants249 Participants25 Participants54 Participants55 Participants
Region of Enrollment
United States
134 participants298 participants31 participants64 participants69 participants
Sex: Female, Male
Female
74 Participants145 Participants13 Participants27 Participants31 Participants
Sex: Female, Male
Male
60 Participants153 Participants18 Participants37 Participants38 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
EG003
affected / at risk
deaths
Total, all-cause mortality
60 / 13437 / 6921 / 6411 / 31
other
Total, other adverse events
134 / 13469 / 6964 / 6431 / 31
serious
Total, serious adverse events
89 / 13441 / 6949 / 6421 / 31

Outcome results

Primary

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

ArmMeasureValue (MEDIAN)
Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])Progression-free Survival (PFS)8.4 months
Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])Progression-free Survival (PFS)3.9 months
Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])Progression-free Survival (PFS)13.8 months
Arm IIb (Placebo, Pancreatic NET Cohort [pNET])Progression-free Survival (PFS)4.4 months
p-value: <0.0001One-sided unstratified log-rank
p-value: <0.0001One-sided unstratified log-rank
Secondary

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

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])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)104 Participants
Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])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)47 Participants
Arm Ib (Cabozantinib S-malate, 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)49 Participants
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)22 Participants
Secondary

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

ArmMeasureValue (MEDIAN)
Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])Overall Survival (OS)21.9 months
Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])Overall Survival (OS)19.7 months
Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])Overall Survival (OS)40.0 months
Arm IIb (Placebo, Pancreatic NET Cohort [pNET])Overall Survival (OS)31.1 months
p-value: 0.2438One-sided stratified log-rank
p-value: 0.4426One-sided stratified log-rank
Secondary

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

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET])Radiographic Response Rate7 Participants
Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET])Radiographic Response Rate0 Participants
Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET])Radiographic Response Rate12 Participants
Arm IIb (Placebo, Pancreatic NET Cohort [pNET])Radiographic Response Rate0 Participants
p-value: 0.05Chi-squared
p-value: 0.01Chi-squared

Source: ClinicalTrials.gov · Data processed: Aug 5, 2026