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

Running, not enrolling · Phase 2

Conditions studied: Differentiated Thyroid Gland Carcinoma, Follicular Variant Thyroid Gland Papillary Carcinoma, Poorly Differentiated Thyroid Gland Carcinoma, Refractory Differentiated Thyroid Gland Carcinoma, Refractory Thyroid Gland Carcinoma, Tall Cell Variant Thyroid Gland Papillary Carcinoma, Thyroid Gland Follicular Carcinoma, Thyroid Gland Oncocytic Carcinoma, Thyroid Gland Papillary Carcinoma

In brief

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.

Key facts

Study ID

NCT03914300

Run by

National Cancer Institute (NCI)

People needed

11

Starts

2020-02-10

Expected to finish

2026-12-17

Last updated by the study team

2026-07-31

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• Patients must have histologically or cytologically confirmed papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), or Hurthle cell thyroid cancer (HTC). Follicular variant of PTC or any of the above mixed histology will be allowed, as well as tall cell, insular, or poorly-differentiated thyroid cancers. Patients with anaplastic thyroid cancers (ATC) or medullary thyroid cancers (MTC) are not eligible
• Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
• Patients must have radioactive iodine (RAI)-refractory/resistant disease as defined by one or more of the following criteria:
• One or more measurable lesions that do not demonstrate RAI uptake,
• Progressive disease (PD) (new lesion or progression of previously known lesions), as defined by RECIST v1.1, within 12 months of prior RAI therapy,
• One or more measurable lesion present after cumulative RAI dose of > 600 mCi, or
• Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan-positive disease (SUV >= 5 in tumor lesion)
• The patient's disease must have progressed on one line of VEGFR-targeted therapy (including, but not limited to, sorafenib, sunitinib, vandetanib, pazopanib, or lenvatinib, etc.) as defined by PD per RECIST v1.1 while receiving VEGFR-targeted therapy. Patients who have received more than one line of prior VEGFR-targeted therapy will not be eligible
• Prior external beam radiation to extra-osseous disease, systemic cytotoxic chemotherapy or BRAF- or non-VEGFR-targeted therapies will be allowed, provided that > 4 weeks has elapsed since receiving prior treatment. Radiation to bone metastases is allowed up to 2 weeks prior to initiation of study treatment
• Patients must be >= 18 years of age. Because no dosing or adverse event data are currently available on the use of XL184 (cabozantinib), nivolumab, or ipilimumab in patients <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.
• Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Patients must have recovered to baseline or =< Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade 1 from toxicities related to any prior treatments, unless adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy
• Absolute neutrophils >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9 g/dL
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN); =< 3.0 x ULN for patients with Gilbert's syndrome
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN
• Alkaline phosphatase =< 3.0 x institutional ULN; =< 5.0 x ULN with documented bone metastases
• Creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula)
• Serum albumin >= 2.8 g/dL
• Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis
• Urine protein/creatinine ratio (UPCR) =< 1 mg/mg
• Serum phosphorus, calcium, magnesium, and potassium within institutional normal limits
• Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) test < 1.3 x ULN
• Patients with a history of human immunodeficiency virus (HIV) infection must be on an effective anti-retroviral regimen utilizing agents that do not strongly induce or inhibit cytochrome P450 (CYP) 3A4, and must have an undetectable viral load measured within 6 months prior to study registration

You may not qualify if…

• Patients must not have had prior treatment with XL184 (cabozantinib), any MET-targeting tyrosine kinase inhibitor (TKI), or any MET-targeting monoclonal antibody (MetMAb), such as onartuzumab
• Patients must not have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways
• Patients must not have a tumor invading or encasing any major blood vessels, and must not have evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum, or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of XL184 (cabozantinib)
• Patients must not have a diagnosis of another malignancy within 2 years before the first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy. Adjuvant hormonal therapy for history of prostate or breast cancer is allowed
• Patients must not have received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 4 weeks, or nitrosoureas/ mitomycin C within 6 weeks, before the first dose of study treatment. Patients may continue on bone-modifying agents (denosumab or bisphosphonates) with caution
• Patients must not have received radiation therapy:
• To the thoracic cavity, abdomen, or pelvis within 4 weeks before the first dose of study treatment;
• To bone metastases within 14 days before the first dose of study treatment;
• To any other sites within 4 weeks before the first dose of study treatment
• Patients must not have clinically relevant, ongoing complications from prior radiation therapy. Palliative (limited-field) radiation therapy is permitted as long as the patient does not have disease progression according to RECIST v 1.1
• Patients must not have received any type of small molecule kinase inhibitor (including investigational kinase inhibitors) within 4 weeks before the first dose of study treatment
• Patients must not have received any other type of investigational agent within 4 weeks before the first dose of study treatment
• Patients must not have a corrected QT interval calculated by the Fridericia formula (QTcF) > 500 msec by electrocardiogram (EKG) within 28 days before the first dose of study treatment
• Note: if a single EKG shows a QTcF with an absolute value > 500 msec, two additional EKGs at intervals of approximately 3 min must be performed within 30 min after the initial EKG, and the average of these three consecutive results for QTcF will be used to determine eligibility
• Patients should not have known, untreated brain metastases or leptomeningeal metastases because of poor prognosis and concerns that progressive neurologic dysfunction could confound the evaluation of neurologic and other adverse events. However, patients will be eligible if metastases have been treated, and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after treatment for metastases is complete and within 28 days prior to the first dose of study treatment
• Patients must not require concomitant treatment with oral anticoagulants (e.g., warfarin, direct thrombin, and factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel). The following anticoagulants are allowed:
• Low-dose aspirin for cardioprotection (per local applicable guidelines),
• Low-dose low molecular weight heparins (LMWH),
• Therapeutic doses of LMWH are allowed in patients without known brain metastases who are on a stable dose of LMWH for at least 6 weeks before the first dose of study treatment, and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor
• Patients must not require systemic corticosteroids treatment (>= 10 mg/day prednisone equivalents) or other immunosuppressive medications within 14 days prior to study drug administration. Inhaled or topical steroids and adrenal replacement doses < 10 mg/day prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if >= 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted, as is steroid pre-medication for contrast allergy
• Patients must not have a history of severe hypersensitivity reactions to any monoclonal antibodies
• Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in study
• Patients must not require concomitant treatment with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, or St. John's wort). Because lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list. Medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, patients will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• Patients must not have uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• Cardiovascular disorders:

Where it is running

• City of Hope Comprehensive Cancer Center — Duarte, California, United States
• Los Angeles General Medical Center — Los Angeles, California, United States
• USC / Norris Comprehensive Cancer Center — Los Angeles, California, United States
• USC Norris Oncology/Hematology-Newport Beach — Newport Beach, California, United States
• Moffitt Cancer Center-International Plaza — Tampa, Florida, United States
• Moffitt Cancer Center - McKinley Campus — Tampa, Florida, United States
• Moffitt Cancer Center — Tampa, Florida, United States
• University of Kansas Clinical Research Center — Fairway, Kansas, United States
• HaysMed — Hays, Kansas, United States
• University of Kansas Cancer Center — Kansas City, Kansas, United States
• The University of Kansas Cancer Center - Olathe — Olathe, Kansas, United States
• University of Kansas Cancer Center-Overland Park — Overland Park, Kansas, United States
• Mercy Hospital Pittsburg — Pittsburg, Kansas, United States
• Salina Regional Health Center — Salina, Kansas, United States
• University of Kansas Health System Saint Francis Campus — Topeka, Kansas, United States
• University of Kansas Hospital-Westwood Cancer Center — Westwood, Kansas, United States
• University of Kentucky/Markey Cancer Center — Lexington, Kentucky, United States
• Mayo Clinic in Rochester — Rochester, Minnesota, United States
• University Health Truman Medical Center — Kansas City, Missouri, United States
• University of Kansas Cancer Center - North — Kansas City, Missouri, United States
• University of Kansas Cancer Center - Lee's Summit — Lee's Summit, Missouri, United States
• University of Kansas Cancer Center at North Kansas City Hospital — North Kansas City, Missouri, United States
• Memorial Sloan Kettering Basking Ridge — Basking Ridge, New Jersey, United States
• Memorial Sloan Kettering Monmouth — Middletown, New Jersey, United States
• Memorial Sloan Kettering Bergen — Montvale, New Jersey, United States

Full record on ClinicalTrials.gov

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