Testing Cabozantinib in Patients With Advanced Pancreatic Neuroendocrine and Carcinoid Tumors

Brief summary public domain (ClinicalTrials.gov)

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 public domain (ClinicalTrials.gov)

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.

Intervention public domain (ClinicalTrials.gov)

Procedure: Biospecimen Collection. Undergo blood and urine sample collection

Intervention public domain (ClinicalTrials.gov)

Drug: Cabozantinib S-malate. Given PO

Intervention public domain (ClinicalTrials.gov)

Procedure: Computed Tomography. Undergo CT

Intervention public domain (ClinicalTrials.gov)

Procedure: Magnetic Resonance Imaging. Undergo MRI

Intervention public domain (ClinicalTrials.gov)

Other: Placebo Administration. Given PO

Intervention public domain (ClinicalTrials.gov)

Other: Quality-of-Life Assessment. Ancillary studies

Intervention public domain (ClinicalTrials.gov)

Procedure: X-Ray Imaging. Undergo x-ray

Arm public domain (ClinicalTrials.gov)

Arm I (cabozantinib S-malate) (experimental): 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.

Arm public domain (ClinicalTrials.gov)

Arm II (placebo) (placebo comparator): 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.

Primary outcome public domain (ClinicalTrials.gov)

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 outcome public domain (ClinicalTrials.gov)

Overall Survival (OS). Time frame: 60 months.

Secondary outcome public domain (ClinicalTrials.gov)

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). Time frame: 60 months.

Secondary outcome public domain (ClinicalTrials.gov)

Radiographic Response Rate. Time frame: 36 months.

Eligibility public domain (ClinicalTrials.gov)

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 …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 298 participants (actual).

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Progression-free Survival (PFS) [36 months]. Median, months (95% Confidence Interval). Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET]) (n=134): 8.4 (7.6 to 12.7); Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET]) (n=69): 3.9 (3.0 to 5.7); Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET]) (n=64): 13.8 (9.2 to 18.5); Arm IIb (Placebo, Pancreatic NET Cohort [pNET]) (n=31): 4.4 (3.0 to 5.9). Analysis, Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET]) vs Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET]): p=<0.0001; One-sided unstratified log-rank; superiority. Analysis, Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET]) vs Arm IIb (Placebo, Pancreatic NET Cohort [pNET]): p=<0.0001; One-sided unstratified log-rank; superiority.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Overall Survival (OS) [60 months]. Median, months (95% Confidence Interval). Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET]) (n=134): 21.9 (18.8 to 30.4); Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET]) (n=69): 19.7 (14.2 to 30.0); Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET]) (n=64): 40.0 (31.3 to NA) [Upper end of the confidence interval is not able to be estimated due to a low number of events]; Arm IIb (Placebo, Pancreatic NET Cohort [pNET]) (n=31): 31.1 (23.4 to NA) [Upper end of the confidence interval is not able to be estimated due to a low number of events]. Analysis, Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET]) vs Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET]): p=0.2438; One-sided stratified log-rank; superiority. Analysis, Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET]) vs Arm IIb (Placebo, Pancreatic NET Cohort [pNET]): p=0.4426; One-sided stratified log-rank; superiority.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

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 months]. Count Of Participants, Participants. Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET]) (n=134): 104; Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET]) (n=69): 47; Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET]) (n=64): 49; Arm IIb (Placebo, Pancreatic NET Cohort [pNET]) (n=31): 22.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Radiographic Response Rate [36 months]. Count Of Participants, Participants. Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET]) (n=134): 7; Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET]) (n=69): 0; Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET]) (n=64): 12; Arm IIb (Placebo, Pancreatic NET Cohort [pNET]) (n=31): 0. Analysis, Arm Ia (Cabozantinib S-malate, Extra-pancreatic NET Cohort [epNET]) vs Arm IIa (Placebo, Extra-pancreatic NET Cohort [epNET]): p=0.05; Chi-squared; superiority. Analysis, Arm Ib (Cabozantinib S-malate, Pancreatic NET Cohort [pNET]) vs Arm IIb (Placebo, Pancreatic NET Cohort [pNET]): p=0.01; Chi-squared; superiority.