Neoplasms

All Conditions

Gland and Hormone Related Diseases

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Carcinoma

Thyroid Neoplasms

Thyroid Cancer, Papillary

Carcinoma, Papillary

Thyroid Diseases

Adenocarcinoma, Follicular

Leukemia-Lymphoma, Adult T-Cell

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Endocrine System Diseases

Endocrine Gland Neoplasms

Head and Neck Neoplasms

Neoplasms, Squamous Cell

Adenocarcinoma, Papillary

Papillary Thyroid Carcinoma

Adult T-cell Leukemia/lymphoma

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Antibodies

Antibodies, Monoclonal

Ipilimumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive cabozantinib S-malate PO QD on days -14 to -1 prior to cycle 1, days 1-42 of cycles 1-4 and days 1-28 of subsequent cycles. Patients also receive nivolumab IV over 30 minutes on days 1, 15, and 29 of cycles 1-4 and day 1 of subsequent cycles and ipilimumab IV over 90 minutes on day 1 of cycles 1-4. Treatment repeats every 42 days for cycles 1-4 and every 28 days for subsequent cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI during screening, and blood sample collection throughout the study.

Biospecimen Collection

Cabozantinib S-malate

Computed Tomography

Magnetic Resonance Imaging

Bhavana Konda

This phase II trial studies how well cabozantinib, nivolumab, and ipilimumab work in treating patients with differentiated thyroid cancer that does not respond to radioactive iodine and that worsened after treatment with a drug targeting the vascular endothelial growth factor receptor (VEGFR), a protein needed to form blood vessels. 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 work better than the usual approach consisting of chemotherapy with drugs such as doxorubicin, sorafenib, and lenvatinib for this type of thyroid cancer.

PRIMARY OBJECTIVE:

I. To assess the objective response rate, defined as the proportion of patients who have had a partial response (PR) or complete response (CR) within the first 6 months after initiation of therapy with cabozantinib S-malate (XL184 \[cabozantinib\]), nivolumab, and ipilimumab (CaboNivoIpi).

SECONDARY OBJECTIVES:

I. To assess duration of objective response (DOR), progression-free survival (PFS), and overall survival (OS).

II. To assess tolerability and adverse events of CaboNivoIpi in patients with differentiated thyroid cancer (DTC).

EXPLORATORY OBJECTIVES:

I. To correlate treatment response (Response Evaluation Criteria in Solid Tumors \[RECIST\] version \[v\]1.1) with tumor mutation status.

II. To correlate treatment response (RECIST v1.1) with frequency of tumor infiltrating lymphocytes in biopsies taken pre-treatment and after 12 weeks of CaboNivoIpi therapy.

III. To evaluate the effect of CaboNivoIpi on T cell receptor (TCR) repertoire and to identify the frequency of shared T cell clones between tumor and peripheral blood.

IV. To evaluate the effect of XL184 (cabozantinib) alone and of the CaboNivoIpi combination on peripheral blood mononuclear cells (PBMCs) and to correlate their frequency with treatment response (RECIST v1.1).

V. To evaluate the effect of XL184 (cabozantinib) alone and of the CaboNivoIpi combination on myeloid-derived suppressor cells (MDSCs) and to correlate their frequency with treatment response (RECIST v1.1).

VI. To correlate treatment response (RECIST v1.1) with programmed cell death protein 1 (PD-1) / programmed cell death-ligand 1 (PD-L1) expression in the primary/metastatic tumor.

OUTLINE:

Patients receive cabozantinib S-malate orally (PO) once daily (QD) on days -14 to -1 prior to cycle 1, days 1-42 of cycles 1-4 and days 1-28 of subsequent cycles. Patients also receive nivolumab intravenously (IV) over 30 minutes on days 1, 15, and 29 of cycles 1-4 and day 1 of subsequent cycles and ipilimumab IV over 90 minutes on day 1 of cycles 1-4. Treatment repeats every 42 days for cycles 1-4 and every 28 days for subsequent cycles in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) during screening, and blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 6 weeks, and then every 12 weeks for up to 2 years.

Testing the Combination of Cabozantinib, Nivolumab, and Ipilimumab (CaboNivoIpi) for Advanced Differentiated Thyroid Cancer

Phase II Study of XL184 (Cabozantinib) in Combination With Nivolumab and Ipilimumab (CaboNivoIpi) in Patients With Radioiodine-Refractory Differentiated Thyroid Cancer Whose Cancer Progressed After One Prior VEGFR-Targeted Therapy

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 using frequency and compared between responders and non-responders using chi-square test or Fisher's exact test, whichever is more appropriate.

Will be described graphically using boxplots or summary measures (e.g., mean and standard errors) at each time point. Will also explore how changes in these correlative markers may differ based on whether or not the patient achieved a response. To accomplish this, will utilize different plotting characters and colors for responses versus (vs.) not in the graphical analyses to help identify potential patterns, and summarize the changes quantitatively between responders and non-responders. Changes in levels will also be compared between responders and non-responders using two sample t-test or Wilcoxon test if the data is not normally distributed. Linear mixed effect models will also be used to examine the association of biomarkers over the time with the response. Potential confounders (patients' demographics and clinical characteristics) may also be included in the models.

Will be described graphically using boxplots or summary measures (e.g., mean and standard errors) at each time point. Will also explore how changes in these correlative markers may differ based on whether or not the patient achieved a response. To accomplish this, will utilize different plotting characters and colors for responses vs. not in the graphical analyses to help identify potential patterns, and summarize the changes quantitatively between responders and non-responders. Changes in levels will also be compared between responders and non-responders using two sample t-test or Wilcoxon test if the data is not normally distributed. Linear mixed effect models will also be used to examine the association of biomarkers over the time with the response. Potential confounders (patients' demographics and clinical characteristics) may also be included in the models.

Defined as the proportion of patients who have had a partial response (PR) or complete response (CR) within the first 6 months after initiation of therapy.

Assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. Frequency and severity of AEs and tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.

Will be analyzed using Kaplan-Meier methods, resulting in median survival times with 95% confidence interval (CI).

Will be analyzed using Kaplan-Meier methods, resulting in median survival times with 95% CI.

National Cancer Institute (NCI)

Symptoms and General Pathology

Recurrence

Carcinoma, Medullary

Carcinoma, Neuroendocrine

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Thyroid Cancer, Medullary

Neuroendocrine Tumor

Neuroepithelioma

Micronutrients

Anti-Infective Agents

Sunitinib

Iodine

Cadexomer iodine

Angiogenesis Inhibitors

Growth Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients receive sunitinib malate PO QD on days 1-28. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity

Laboratory Biomarker Analysis

Pharmacogenomic Study

Sunitinib Malate

Tanguy Y Seiwert

This phase II trial studies how well sunitinib malate works in treating patients with thyroid cancer that did not respond to iodine I 131 (radioactive iodine) and cannot be removed by surgery. Sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PRIMARY OBJECTIVES:

I. Determine the response rate of single agent sunitinib (sunitinib malate) in patients with iodine refractory, unresectable well-differentiated thyroid cancer (WDTC) who have evidence of disease progression within 6 months of study enrollment.

II. Determine the response rate of single agent sunitinib in patients with medullary thyroid cancer (MTC) who have evidence of disease progression within 6 months of study enrollment.

III. Determine the toxicity, duration of response, progression free survival, and overall survival in patients with WDTC or MTC treated with single agent sunitinib.

IV. Determine whether the presence of ret proto-oncogene (RET) gene rearrangements in patients with WDTC or RET mutations in patients with MTC predict response to sunitinib.

V. Determine whether therapy with sunitinib affects phosphorylation of downstream RET effector, mitogen-activated protein kinase 1 (ERK), in WDTC and MTC tissue.

VI. Determine whether specific germ-line polymorphisms in the RET gene are associated with favorable outcome in patients with WDTC treated with sunitinib.

OUTLINE: Patients are assigned to 1 of 2 cohorts according to type of thyroid cancer (medullary vs well-differentiated).

Patients receive sunitinib malate orally (PO) once daily (QD) on days 1-28. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 2 years.

Sunitinib Malate in Treating Patients With Thyroid Cancer That Did Not Respond to Iodine I 131 and Cannot Be Removed by Surgery

Phase II Trial of Sunitinib (SU11248) in Iodine-131 Refractory, Unresectable Differentiated Thyroid Cancers and Medullary Thyroid Cancers

Relevant laboratory correlates will be compared between responders and non-responders using the Wilcoxon rank sum test. The association between the presence or absence of RET gene rearrangements/mutations and tumor response, as well as the association between germ-line polymorphisms in the RET gene and response, will be analyzed using Fisher's exact test. The correlative and genetic data will also be entered as covariates (univariate analyses only due to the small sample size) in a Cox regression model of progression-free survival.

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT or 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."

Any grade toxicity of any type, regardless of attribution

Kaplan-Meier curves will be generated and 95% confidence intervals will be derived for median overall survival.

Patients receive sunitinib malate PO QD on days 1-28. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity

This arm contains results for the Radioactive Iodine Refractory Thyroid Cancer Subgroup

Sunitinib Malate: Given PO

Sunitinib Malate-Radioactive Iodine Refractory Subgroup

Patients receive sunitinib malate PO QD on days 1-28. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity

This arm contains results for the Metastatic Medullary Thyroid Cancer Subgroup

Sunitinib Malate: Given PO

Sunitinib Malate-Metastatic Medullary Subgroup

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Tanguy Seiwert

Note. The objective was not to compare the two arms (subgroups), but to compare each with historical data.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Testing the Combination of Cabozantinib, Nivolumab, and Ipilimumab (CaboNivoIpi) for Advanced Differentiated Thyroid Cancer	NCT03914300	Differentiated ... Follicular Vari... Poorly Differen... Refractory Diff... Refractory Thyr... Tall Cell Varia... Thyroid Gland F... Thyroid Gland O... Thyroid Gland P...	Biospecimen Col... Cabozantinib S-... Computed Tomogr... Ipilimumab Magnetic Resona... Nivolumab	18 Years -	National Cancer Institute (NCI)
Sunitinib Malate in Treating Patients With Thyroid Cancer That Did Not Respond to Iodine I 131 and Cannot Be Removed by Surgery	NCT00381641	Differentiated ... Recurrent Thyro... Refractory Thyr... Stage III Thyro... Stage III Thyro... Stage IV Thyroi... Stage IV Thyroi... Stage IV Thyroi... Stage IVA Thyro... Stage IVA Thyro... Stage IVA Thyro... Stage IVB Thyro... Stage IVB Thyro... Stage IVB Thyro... Stage IVC Thyro... Stage IVC Thyro... Stage IVC Thyro... Thyroid Gland O... Unresectable Th...	Laboratory Biom... Pharmacogenomic... Sunitinib Sunitinib Malat...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for thyroid gland oncocytic carcinoma