| Eligibility |
Inclusion Criteria:
- 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
- Patients with evidence of chronic hepatitis B virus (HBV) infection must have
undetectable HBV viral load on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. Patients with HCV infection who are currently on treatment are eligible if
they have an undetectable HCV viral load
- The effects of XL184 (cabozantinib), nivolumab, and ipilimumab on the developing human
fetus are unknown. For this reason, women of child-bearing potential (WOCBP) and men
must agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation. WOCBP
should use an adequate method to avoid pregnancy for 5 months after the last dose of
study therapy. Women of childbearing potential must have a negative serum or urine
pregnancy test (minimum sensitivity: 25 IU/L or equivalent units of human chorionic
gonadotropin [hCG]) within 24 hours prior to the start of study therapy. Women must
not be breastfeeding. Men who are sexually active with WOCBP must use any
contraceptive method with a failure rate of < 1% per year. Men who receive study
therapy and who are sexually active with WOCBP will be instructed to adhere to
contraception for a period of 7 months after the last dose of study therapy. Women who
are not of childbearing potential (i.e., who are postmenopausal or surgically sterile)
as well as azoospermic men do not require contraception
- WOCBP is defined as any female who has experienced menarche and who has not undergone
surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not
postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman
over 45 in the absence of other biological or physiological causes. In addition, women
under the age of 55 must have a documented serum follicle stimulating hormone (FSH)
level < 40 mIU/mL
- WOCBP and men who are sexually active with WOCBP will be instructed to adhere to
contraception for a period of 5 and 7 months, respectively, after the last dose of
study therapy. These durations have been calculated using the upper limit of the
half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP
use contraception for 5 half-lives plus 30 days and men who are sexually active with
WOCBP use contraception for 5 half-lives plus 90 days
- Should a woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she (or the participating partner) must inform the
treating physician immediately
- Patients must be able to swallow tablets
- Patients must be able to understand be willing to sign a written informed consent
document
- Patients with impaired decision-making capacity (IDMC) will be eligible if they have a
legally authorized representative (LAR) or caregiver available to assist them
Exclusion Criteria:
- 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:
- Congestive heart failure New York Heart Association (NYHA) class 3 or 4,
unstable angina pectoris, serious cardiac arrhythmias
- Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm
Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive
treatment within seven days prior to the first dose of study treatment
- Stroke (including transient ischemic attack [TIA]), myocardial infarction
(MI), or other ischemic event, or thromboembolic event (e.g., deep venous
thrombosis [DVT], pulmonary embolism [PE]) within 6 months before first dose
- GI disorders including those associated with a high risk of perforation or
fistula formation:
- The patient has evidence of tumor invading the GI tract, active peptic ulcer
disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis,
cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis,
acute obstruction of the pancreatic duct or common bile duct, or gastric
outlet obstruction
- Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal
abscess within 6 months before first dose. Complete healing of an
intra-abdominal abscess must be confirmed before first dose
- Clinically significant hematuria, hematemesis, or hemoptysis or other history of
significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first
dose
- Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
manifestation
- Lesions invading or encasing any major blood vessels
- Other clinically significant disorders that would preclude safe study
participation
- Serious non-healing wound/ulcer/bone fracture
- Uncompensated/symptomatic hypothyroidism
- Moderate to severe hepatic impairment (Child-Pugh B or C)
- Patients must not have had major surgery (e.g., GI surgery or removal or biopsy of
brain metastasis) within 8 weeks before first dose of study treatment. Complete wound
healing from major surgery must have occurred 1 month before the first dose of study
treatment and from minor surgery (e.g., simple excision or tooth extraction) at least
10 days before the first dose. Patients with clinically relevant ongoing complications
from prior surgery are not eligible
- Pregnant women are excluded from this study because XL184 (cabozantinib) has the
potential for teratogenic or abortifacient effects, and the effects of nivolumab and
ipilimumab on the developing fetus are not well known. Because there is an unknown but
potential risk for AEs in nursing infants secondary to treatment of the mother,
breastfeeding must be discontinued if the mother is treated with XL184 (cabozantinib),
nivolumab, or ipilimumab
- Patients with active autoimmune disease or history of autoimmune disease that might
recur, which may affect vital organ function or require immune suppressive treatment
including high dose systemic corticosteroids, should be excluded. These include but
are not limited to: immune-related neurologic disease, such as multiple sclerosis,
autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, or myasthenia gravis;
systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective
tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative
colitis, or autoimmune hepatitis. Patients with a history of toxic epidermal
necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be
excluded because of the risk of recurrence or exacerbation of disease. Patients with
vitiligo, type I diabetes mellitus (DM), or endocrine deficiencies (e.g., thyroiditis)
managed with replacement hormones, including physiologic corticosteroids, are eligible
- Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and
psoriasis controlled with topical medication, and patients with positive serology,
(e.g., antinuclear antibodies [ANA] or anti-thyroid antibodies) should be evaluated
for the presence of target organ involvement and potential need for systemic treatment
but should otherwise be eligible
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