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

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