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

Disease Attributes

Pembrolizumab

Lenvatinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients receive lenvatinib PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 19 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment for up to 35 cycles.

Laboratory Biomarker Analysis

Lenvatinib Mesylate

Bryan R Haugen

This phase II trial studies how well pembrolizumab and lenvatinib work in treating patients with differentiated thyroid cancer that has spread to other places in the body or has come back and cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

PRIMARY OBJECTIVES:

I. To investigate the clinical efficacy, as indicated by the rate of complete response (CR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, of combination therapy with pembrolizumab and lenvatinib in lenvatinib-naive patients with progressive radioiodine-refractory differentiated thyroid cancers (DTC). (Cohort 1) II. To determine the overall response rate (ORR) by the addition of pembrolizumab to patients with radioiodine-refractory DTC who have progressive disease on lenvatinib alone. (Cohort 2)

SECONDARY OBJECTIVES:

I. To determine the safety profile and toxicity of combination therapy with pembrolizumab and lenvatinib in patients with progressive DTC. (Cohort 1 and cohort 2) II. To determine progression-free survival (PFS) and overall survival (OS). (Cohort 1 and cohort 2)

CORRELATIVE RESEARCH OBJECTIVES:

I. To correlate tumor response (RECIST 1.1) with pretreatment frequency of CD8+ T cells in the primary and/or metastatic tumor. (Cohort 1 and cohort 2) II. To correlate tumor response (RECIST 1.1) with pretreatment PD-L1 and PD-L2 levels in the primary and/or metastatic tumor. (Cohort 1 and cohort 2) III. To correlate tumor response (RECIST 1.1) with pretreatment frequency of lymphocytes expressing CD3, CD4, PD-1, FoxP3, or CD20, and of CD163+ macrophages. (Cohort 1 and cohort 2) IV. To correlate tumor response (RECIST 1.1) with the phenotype and frequency of key leukocyte subsets (i.e., PD-1+ T cells, regulatory T cells \[Tregs\], myeloid subsets) in the peripheral blood before, at 6 and 18 weeks on therapy, and at 54 weeks (study completion), progressive disease (PD), or study withdrawal. (Cohort 1) V. To correlate tumor response (RECIST 1.1) with PD-1+ T cell functional capacity. (Cohort 1) VI. To correlate tumor response (RECIST 1.1) with serum anti-thyroglobulin antibody levels assessed before, and at 18 weeks on therapy. (Cohort 1 and 2) VII. To correlate tumor response (RECIST 1.1) with tumor mutation status. (Cohort 1) VIII. To broadly investigate mechanisms of response and resistance to combination therapy, gene expression profiles will be generated from frozen biopsies for analysis by ribonucleic acid-sequencing (RNA-Seq). (Cohort 1)

OUTLINE:

Patients receive lenvatinib orally (PO) once daily (QD) on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 19 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment for up to 35 cycles.

After completion of study treatment, patients are followed up every 3 months for up to 3 years.

Lenvatinib and Pembrolizumab in Differentiated Thyroid Cancers (DTC)

Combination Targeted Therapy With Pembrolizumab and Lenvatinib in Progressive, Radioiodine-Refractory Differentiated Thyroid Cancers: A Phase II Study

All analyses with respect to the translational component of this study are intended to be hypothesis-generating and descriptive in manner. Clinical data (i.e. CR rates confirmed response rates, PFS, OS, etc.) will be correlated with tumor marker data of interest (CD8+, PD-L1, PD-L2, T cell functional capacity markers, anti-thyroglobulin antibody levels, tumor mutation status, and other markers). The Chi-Square (or Fisher's Exact test) will be used to assess the association of categorical clinical data with categorical biomarker data. Time-to-event clinical data (PFS, OS) will be correlated with biomarker data using Kaplan-Meier methodology and Cox regression models. Logistic regression models will also be used to predict binary clinical data with baseline biomarker data. Finally, graphical methods and descriptive statistics will be used to summarize the data as well. Two-sided p-values \< 0.05 will be considered statistically significant.

Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will use a one-stage binomial design.

Assessed by RECIST 1.1. Will use a 2-stage Simon Optimal MinMax design.

Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. All patients that have initiated treatment will be considered evaluable for assessing adverse events. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns. Only the grade 2+ adverse events will be assessed, regardless of relationship to the study treatment.

The distribution of PFS will be estimated using the method of Kaplan-Meier.

The distribution of survival at 12 months will be estimated using the method of Kaplan-Meier.

Academic and Community Cancer Research United

All patients that began treatment were assessed for adverse events

Cohort 1

Cohort 2

Lenvatinib-naïve patients\> Patients receive lenvatinib 20mg PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 19 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment for up to 35 cycles.\> \> Laboratory Biomarker Analysis: Correlative studies\>

\> Lenvatinib: Given PO\>

\> Lenvatinib Mesylate: Given PO\>

\> Pembrolizumab: Given IV

Previously progressed on Lenvatinib alone\> Patients receive lenvatinib daily dose at progression QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 19 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment for up to 35 cycles.\> \> Laboratory Biomarker Analysis: Correlative studies\>

\> Lenvatinib: Given PO\>

\> Lenvatinib Mesylate: Given PO\>

\> Pembrolizumab: Given IV

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Prior systemic VEGFR-active kinase inhibitor therapy

Histologic subtype of primary tumor

ECOG Performance Status

All enrolled patients were included in baseline analysis

Bryan Haugen, M.D.

All evaluable patients in cohort 1 were analyzed for this endpoint.

Complete Response Rate (Cohort 1)

All evaluable patients in cohort 2 were analyzed for this endpoint.

Confirmed Response Rate (Cohort 2)

Lenvatinib-naïve patients

\> Patients receive lenvatinib 20mg PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 19 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment for up to 35 cycles.

\>

\> Laboratory Biomarker Analysis: Correlative studies

\>

\> Lenvatinib: Given PO

\>

\> Lenvatinib Mesylate: Given PO

\>

\> Pembrolizumab: Given IV

Previously progressed on Lenvatinib alone

\> Patients receive lenvatinib daily dose at progression QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 19 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment for up to 35 cycles.

\>

\> Laboratory Biomarker Analysis: Correlative studies

\>

\> Lenvatinib: Given PO

\>

\> Lenvatinib Mesylate: Given PO

\>

\> Pembrolizumab: Given IV

All evaluable patients were analyzed for this endpoint.

Number of Patients Experiencing Grade 3+ Adverse Events

Progression Free Survival (PFS)

Overall Survival (OS)

Biomarker Levels Analysis Following Pembrolizumab and Lenvatinib Combination Therapy

Overall Study

Patients receive cabozantinib-s-malate PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Manisha Shah

This phase II trial studies how well cabozantinib-s-malate works in treating patients with thyroid cancer that does not respond to treatment. Cabozantinib-s-malate may stop the growth of thyroid cancer by blocking some of the enzymes needed for cell growth. Cabozantinib-s-malate may also stop the growth of thyroid cancer by blocking blood flow to the tumor.

PRIMARY OBJECTIVES:

I. 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 (cabozantinib-s-malate).

SECONDARY OBJECTIVES:

I. To assess duration of objective response, progression-free survival and overall survival.

II. To assess tolerability and adverse events of cabozantinib as a 2nd line therapy in patients with differentiated thyroid cancer (DTC).

TERTIARY OBJECTIVES:

I. To assess effect of cabozantinib on serum tumor marker thyroglobulin and its correlation with overall response rate.

II. To assess response of cabozantinib in bone metastasis (bone metastasis-specific progression free survival) as evaluated by pre- and on-study functional imaging such as bone scan, fludeoxyglucose F 18 (18F-FDG) positron emission tomography (PET) scan and/or 18F sodium fluoride (NaF) PET scan.

III. To assess effect of cabozantinib on serum and urinary markers of bone turnover and its correlation with response to bone metastasis.

IV. To assess predictors of response by performing tumor genotype studies (e.g. v-raf murine sarcoma viral oncogene homolog B \[BRAF\], rat sarcoma \[RAS\], phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha \[PIK3CA\], mitogen-activated protein kinase 1 \[MAP2K1\], v-akt murine thymoma viral oncogene homolog 1 \[AKT1\], mesenchymal-epithelial transition \[MET\], rearranged in transformation \[RET\]/papillary thyroid carcinoma \[PTC\] rearrangement) in archived tumor tissue.

V. To assess predictors of response by assessing baseline expression levels of vascular endothelial growth factor (VEGF), phosphorylated vascular endothelial growth factor receptor (pVEGFR), phosphorylated mitogen-activated protein kinase 1 (pERK), phosphorylated AKT1 (pAKT) and/or total met proto-oncogene (MET) by immunohistochemistry in archived tumor tissue.

OUTLINE:

Patients receive cabozantinib-s-malate orally (PO) daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks and then every 3 months for 1 year.

Cabozantinib-S-Malate in Treating Patients With Refractory Thyroid Cancer

Phase II Study of Cabozantinib in Patients With Radioiodine-Refractory Differentiated Thyroid Cancer Who Progressed on Prior VEGFR-Targeted Therapy

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) 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

Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

These baseline levels will be quantitatively summarized and graphically explored, in particular in terms of how they relate to clinical outcomes of interest. Analyses exploring differences in these angiogenic and correlative markers in relation to clinical outcomes will be largely hypothesis-generating. With limited numbers of patients patterns of difference will primarily be looked for using graphical analyses; these can include plots of these marker levels in relation to clinical outcomes to identify potential patterns of interest.

The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. Tolerability of the regimens will be assessed through assessing the number of patients who required dose modifications and/or dose delays. In addition, the proportion of patients who go off treatment due to adverse reactions or even those who refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial will be captured.

Side-by-side boxplots will be used to assess possible differences in this change between responders and non-responders, and scatterplots can assess the influence of baseline thyroglobulin levels on these measures of change.

Exelixis

The National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 was utilized for Adverse event reporting.

Patients receive cabozantinib-s-malate PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cabozantinib S-malate: Given PO

Laboratory Biomarker Analysis: Correlative studies

Treatment (Cabozantinib-s-malate)

Patients receive Cabozantinib 60mg PO QD with dose escalation to 80mg QD or dose reduction to 40mg daily or 20mg. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Manisha Shah, MD

Objective Response Rate, Defined as the Proportion of Patients Who Have Had a PR or CR as Assessed by the RECIST Version (v)1.1

Data not collected to be analyzed at this time

Bone Turnover, as Measured by Serum and Urinary Markers of Bone Turnover

Duration of Objective Response as Assessed by the RECIST v1.1

Data has not been collected and analyzed at this time

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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)
Lenvatinib and Pembrolizumab in Differentiated Thyroid Cancers (DTC)	NCT02973997	Columnar Cell V... Follicular Vari... Metastatic Thyr... Metastatic Thyr... Poorly Differen... Recurrent Diffe... Recurrent Thyro... Recurrent Thyro... Stage III Diffe... Stage III Thyro... Stage III Thyro... Stage IV Thyroi... Stage IV Thyroi... Stage IVA Diffe... Stage IVA Thyro... Stage IVA Thyro... Stage IVB Diffe... Stage IVB Thyro... Stage IVB Thyro... Stage IVC Diffe... Stage IVC Thyro... Stage IVC Thyro... Tall Cell Varia... Thyroid Gland H... Unresectable Di... Unresectable Th...	Laboratory Biom... Lenvatinib Lenvatinib Mesy... Pembrolizumab	18 Years -	Academic and Community Cancer Research United
Cabozantinib-S-Malate in Treating Patients With Refractory Thyroid Cancer	NCT01811212	Poorly Differen... Recurrent Thyro... Stage I Thyroid... Stage I Thyroid... Stage II Thyroi... Stage II Thyroi... Stage III Thyro... Stage III Thyro... Stage IVA Thyro... Stage IVA Thyro... Stage IVB Thyro... Stage IVB Thyro... Stage IVC Thyro... Stage IVC Thyro... Tall Cell Varia... Thyroid Gland O...	Cabozantinib S-... Laboratory Biom...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for tall cell variant thyroid gland papillary carcinoma