Neoplasms

All Conditions

Rare Diseases

Carcinoma

Neuroendocrine Tumors

Carcinoma, Neuroendocrine

Carcinoma, Small Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Adenocarcinoma

Neoplasms, Nerve Tissue

Neuroendocrine Tumor

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Nivolumab

Ipilimumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive cabozantinib s-malate PO QD on days 1-21 of cycles 1-4 and days 1-28 of subsequent cycles, nivolumab IV over 30 minutes on day 1, and ipilimumab IV over 90 minutes on day 1 of cycles 1-4 only. Treatment repeats every 21 for 4 cycles then every 28 days for subsequent cycles in the absence of disease progression or unacceptable toxicity.

Cabozantinib S-malate

Anteneh A Tesfaye

This phase II trial studies how well the combination of XL184 (cabozantinib), nivolumab, and ipilimumab work in treating patients with poorly differentiated neuroendocrine tumors (i.e., neuroendocrine tumor that does not look like the normal tissue it arose from). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving cabozantinib, nivolumab and ipilimumab may shrink the cancer.

PRIMARY OBJECTIVE:

I. To evaluate the overall response rate (ORR) associated with the combination of XL184 (cabozantinib), nivolumab, and ipilimumab in patients with advanced poorly-differentiated neuroendocrine carcinomas (NECs), after the failure of at least one line of prior therapy.

SECONDARY OBJECTIVES:

I. To evaluate progression-free survival (PFS). II. To measure the safety and tolerability of the combination of XL184 (cabozantinib), nivolumab, and ipilimumab in patients with advanced, poorly-differentiated NECs.

III. To evaluate disease control rate (DCR). IV. To measure duration of response (DOR). V. To describe the tumor molecular profile using whole exome sequencing (WES) and correlate it with treatment outcome.

VI. To describe the tumor molecular profile using ribonucleic acid (RNA) sequencing (RNAseq) and correlate it with treatment outcome.

EXPLORATORY OBJECTIVES:

I. To measure the tumor-infiltrating CD8+ T lymphocytes in pre- and on-treatment biopsies.

II. To measure tumor-infiltrating myeloid derived suppressor cells (MDSCs) in pre- and on-treatment biopsies.

III. To measure tumor-infiltrating tumor-associated macrophages (TAM) in the pre and on-treatment biopsies.

IV. To measure the expression of programmed death-ligand 1 (PD-L1) in tumor cells and infiltrating immune cells.

OUTLINE:

Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-21 of cycles 1-4 and days 1-28 of subsequent cycles, nivolumab intravenously (IV) over 30 minutes on day 1, and ipilimumab IV over 90 minutes on day 1 of cycles 1-4 only. Treatment repeats every 21 for 4 cycles then every 28 days for subsequent cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks, and then every 3 months thereafter.

Testing the Combination of XL184 (Cabozantinib), Nivolumab, and Ipilimumab for Poorly Differentiated Neuroendocrine Tumors

A Phase 2 Study of XL184 (Cabozantinib) in Combination With Nivolumab and Ipilimumab for the Treatment of Poorly Differentiated Neuroendocrine Carcinomas

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Will be summarized with descriptive statistics (N, mean, standard deviation, median, interquartile range \[IQR\], minimum, maximum, and a CI for the mean). Statistical graphics (e.g., box plots, dot plots, etc.) will also be created to illustrate the distributions of the various correlative endpoints.

Will be summarized with descriptive statistics (N, mean, standard deviation, median, IQR, minimum, maximum, and a CI for the mean). Statistical graphics (e.g., box plots, dot plots, etc.) will also be created to illustrate the distributions of the various correlative endpoints.

Defined as complete responses (CR) plus partial responses (PR). Responses will be determined via Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. CR+PR rate will be summarized with a point estimate and a 2-sided Wilson type confidence interval (CI) estimate.

Analyzed with standard Kaplan-Meier methodology. Point and CI estimates of the median and various time point-specific rates will be derived from the Kaplan-Meier life table. Censored PFS will be analyzed for all registered patients.

Safety including specific toxicity types, grades, and attributions will be evaluated and summarized. Toxicity will be assessed in all toxicity-evaluable (t-e) patients using the Common Terminology Criteria for Adverse Events (CTCAE) 5.0 criteria. The t-e population is defined as all patients who have received the study treatment. The resulting binary endpoints of each toxicity type at a specific grade(s), will all be summarized with point estimates and 2-sided Wilson type CI estimates. The grade of each type of toxicity will also be summarized with 1-way frequency distributions.

The binary endpoint of DCR will be defined as the achievement of either CR, or PR, or stable disease (SD) (yes/no). The resulting binary endpoints of DCR will all be summarized with point estimates and 2-sided Wilson type CI estimates.

The censored time-to-event distributions of DOR will be analyzed with standard Kaplan-Meier methodology. Point and CI estimates of the median and various time point-specific rates will be derived from the Kaplan-Meier life table. Censored DOR will be analyzed for the combination of all patients who achieve either a CR or a PR.

National Cancer Institute (NCI)

Heart and Blood Diseases

Heart Diseases

Carcinoid Tumor

Carcinoid Heart Disease

Patients receive telotristat ethyl PO TID and SSA for 6 months in the absence of disease progression or unacceptable toxicity.

Patients receive placebo PO TID and SSA for 6 months in the absence of disease progression or unacceptable toxicity.

Placebo Administration

Questionnaire Administration

Telotristat Ethyl

Cezar A. Iliescu, MD

Cezar Iliescu, MD

Cezar A Iliescu, MD

This phase III trial compares the effect of telotristat ethyl and the current standard of care somatostatin analog therapy or somatostatin analog therapy alone in treating patients with neuroendocrine tumor that has spread to other places in the body (metastatic). Telotristat ethyl and somatostatin analog therapy may help to control carcinoid syndrome and carcinoid heart disease.

PRIMARY OBJECTIVE:

I. To estimate the percent change in N-terminal pro B-type natriuretic peptide (NT-proBNP) at 6 month visit from baseline after initiation of study drug in each arm and to compare the percent change between the two study arms.

SECONDARY OBJECTIVES:

I. To evaluate the change in functional capacity from baseline at 3 and 6 month visits as assessed by a 6 minute walk test (6MWT) in each arm.

II. To evaluate changes in echocardiographic parameters (Carcinoid Valvular Heart Disease \[CVHD\] score, global longitudinal myocardial strain assessment of the left and right ventricle/tricuspid annular plane systolic excursion \[TAPSE\]) from baseline to 3 and 6 month visits in each arm.

III. To evaluate the change from baseline to 3 and 6 month visits in plasma 5-hydroxyindoleacetic acid (5-HIAA) levels in each arm.

IV. To evaluate the change from baseline to 3 and 6 month visits in high sensitivity troponin T in each arm.

V. To evaluate the change from baseline to 3 and 6 month visits in health related quality of life with using the MD Anderson Symptom Inventory (MDASI) in each arm.

VI. To evaluate compliance of medications.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive telotristat ethyl orally (PO) three times daily (TID) and somatostatin analog therapy (SSA) for 6 months in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive placebo PO TID and SSA for 6 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Testing the Combination of XL184 (Cabozantinib), Nivolumab, and Ipilimumab for Poorly Differentiated Neuroendocrine Tumors	NCT04079712	Metastatic Larg... Metastatic Neur... Metastatic Neur... Metastatic Smal...	Cabozantinib S-... Ipilimumab Nivolumab	18 Years -	National Cancer Institute (NCI)
Telotristat Ethyl for the Treatment of Carcinoid Heart Disease in Patients With Metastatic Neuroendocrine Tumor	NCT04810091	Locally Advance... Metastatic Neur...	Placebo Adminis... Questionnaire A... Telotristat Eth...	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for metastatic neuroendocrine neoplasm