Neoplasms

All Conditions

Blood and Lymph Conditions

Digestive System Diseases

Gland and Hormone Related Diseases

Rare Diseases

Neuroendocrine Tumors

Thymoma

Thymus Neoplasms

Adenoma

Adenoma, Islet Cell

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Neoplasms, Glandular and Epithelial

Pancreatic Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Thoracic Neoplasms

Lymphatic Diseases

Neuroendocrine Tumor

Pancreatic Neuroendocrine Tumor

Non Functioning Pancreatic Endocrine Tumor

Functioning Pancreatic Endocrine Tumor

Neuroepithelioma

Pancreatic Cancer

Patients receive ribociclib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Pharmacological Study

Ribociclib

Nageshwara V Dasari

This phase II trial studies how well ribociclib works in treating patients with neuroendocrine tumors of the foregut, which includes the thymus, lung, stomach, and pancreas, that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced tumors). Ribociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To estimate the Response Evaluation Criteria in Solid Tumors (RECIST) (per version 1.1) objective response rate of LEE011 (ribociclib) among patients with advanced foregut neuroendocrine tumors (NETs).

SECONDARY OBJECTIVES:

I. To evaluate the progression free survival duration of LEE011 among patients with advanced foregut NETs.

II. To evaluate the safety and tolerability of LEE011 in patients with advanced foregut NETs.

III. To determine clinic benefit rate at 6 months (defined as complete response plus partial response plus stable disease) with LEE011 among patients with advanced foregut NETs.

EXPLORATORY OBJECTIVES:

I. To determine baseline molecular markers (mutations, deletions, and amplifications in multiple endocrine neoplasia \[MEN\]1, p27, p16 and cyclin D1 \[CCND1\]) in archival tumor that may predict clinical benefit at 6 months from LEE011.

II. To determine potential mechanisms/markers of resistance. III. To determine early chromogranin and neuron specific enolase responses in patients with elevated levels at baseline.

IV. To determine the pharmacodynamic changes including proliferation-related Ki-67 antigen (Ki-67) and phosphorylated retinoblastoma (pRb) upon treatment with LEE011 in patients with advanced foregut NETs.

OUTLINE:

Patients receive ribociclib orally (PO) once daily (QD) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Ribociclib in Treating Patients With Advanced Neuroendocrine Tumors of Foregut Origin

A Phase II Study of LEE011 (Ribociclib) in Patients With Advanced Neuroendocrine Tumors of Foregut Origin

Decrease in pRB as Measured by Immunohistochemistry (IHC) in Biopsies From Baseline and From cycle 2 day 1. H-scores were calculated as the sum of the products of the percentage of positive staining areas and the staining intensity (0, 1, 2 or 3), and ranged from 0 to 300. A score of 0 represents the absence of expression, and an H-score of 300 represents maximum expression.

Ki-67 was calculated as a percentage cells staining positive by Immunohistochemistry (IHC).

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Number of Participants that did not have progressive disease at 6 months.

PFS is the length of time during and after the treatment that a participant lives with the disease but it does not get worse.The Kaplan-Meier (KM) method will be used to estimate the PFS.

National Cancer Institute (NCI)

Novartis

M.D. Anderson Cancer Center

LEE011 will be taken orally, once a day for 21 consecutive days followed by a 7 day planned break. LEE011 will be dosed on a flat dosing scale of 600 mg/day, irrespective of size and weight.

Study Participants

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Arvind Dasari,MBBS

Number of Participants With Response Rate Per Response Evaluation Criteria in Solid Tumors Version 1.1

Number of Participants With Clinical Benefit Rate

Progression Free Survival (PFS)

H- Score Pre-Treatment

H-Score Post-Treatment

Change in pRB With Treatment

Pre-Treatment

Post-Treatment

Change in Ki-67 With Treatment

Overall Study

Symptoms and General Pathology

Substance Related Disorders

Disease Progression

Carcinoid Tumor

Intestinal Neoplasms

Stomach Neoplasms

Syndrome

Malignant Carcinoid Syndrome

Serotonin Syndrome

Adenocarcinoma

Carcinoma

Intestinal Diseases

Stomach Diseases

Gastro-enteropancreatic Neuroendocrine Tumor

Stomach Cancer

Carcinoid Syndrome

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.

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.

Cabozantinib S-malate

Computed Tomography

Magnetic Resonance Imaging

Placebo Administration

Quality-of-Life Assessment

X-Ray Imaging

Jennifer A Chan

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 S-malate (cabozantinib) 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 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 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.

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)

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.

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.

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Ribociclib in Treating Patients With Advanced Neuroendocrine Tumors of Foregut Origin	NCT02420691	Advanced Digest... Duodenal Neuroe... Functional Panc... Gastric Neuroen... Intermediate Gr... Low Grade Lung ... Nonfunctional P... Thymus Neoplasm	Laboratory Biom... Pharmacological... Ribociclib	18 Years -	M.D. Anderson Cancer Center
Testing Cabozantinib in Patients With Advanced Pancreatic Neuroendocrine and Carcinoid Tumors	NCT03375320	Carcinoid Tumor Functioning Pan... Intermediate Gr... Locally Advance... Locally Advance... Locally Advance... Locally Advance... Locally Advance... Low Grade Lung ... Lung Neuroendoc... Lung Neuroendoc... Metastatic Dige... Metastatic Dige... Metastatic Lung... Metastatic Lung... Metastatic Panc... Metastatic Panc... Metastatic Thym... Neuroendocrine ... Neuroendocrine ... Non-Functioning... Pancreatic Sero... Thymic Neuroend... Unresectable Di... Unresectable Di... Unresectable Lu... Unresectable Pa... Unresectable Th...	Cabozantinib S-... Computed Tomogr... Magnetic Resona... Placebo Adminis... Quality-of-Life... X-Ray Imaging	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for intermediate grade lung neuroendocrine neoplasm