Testing the Combination of the Anti-cancer Drugs XL184 (Cabozantinib) and Nivolumab in Patients With Advanced Cancer and HIV

  • STATUS
    Recruiting
  • End date
    Nov 2, 2025
  • participants needed
    18
  • sponsor
    National Cancer Institute (NCI)
Updated on 24 October 2021
cancer
hysterectomy
immunodeficiency
antiretroviral
antiretroviral therapy
hiv test
hepatitis
HIV Vaccine
investigational new drug
enzyme-linked immunosorbent assay

Summary

This phase I trial investigates the side effects of cabozantinib and nivolumab in treating patients with cancer that has spread to other places in the body (advanced) and who are undergoing treatment for human immunodeficiency virus (HIV). 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, 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 and nivolumab may shrink or stabilize cancer in patients undergoing treatment for HIV.

Description

PRIMARY OBJECTIVES:

I. To determine the safety of combined nivolumab and cabozantinib s-malate (XL184 [cabozantinib]) in human immunodeficiency virus (HIV) patients with advanced solid tumors.

II. To determine the feasibility to deliver the combined nivolumab and XL184 (cabozantinib) for a minimum of 4 cycles in at least 75% of the subjects in the expanded cohort with Kaposi sarcoma (KS) or to achieve a confirmed objective response.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity in subjects with Kaposi Sarcoma (KS).

II. To assess the effect of treatment on participants' immune status (CD4 and CD8 cell counts) and HIV viral loads.

III. To preliminarily evaluate the objective response rate (ORR) to the combination treatment in subjects with KS.

EXPLORATORY OBJECTIVES:

I. To assess duration of response (DOR), progression-free survival (PFS), and overall survival (OS) in subjects with KS.

II. To assess the PD-L1 immunohistochemistry (IHC) status in tumors and tumor microenvironment and its association with clinical outcome.

III. To assess the expression characteristics and cellular distribution of immune checkpoints (PD-L1, B7x, HHLA2, B7H3), infiltrating immune cells (CD4 T cells, CD8 T cells, regulatory T-cells [Tregs], myeloid-derived suppressor cell [MDSC]), and other tumor microenvironment biomarkers (VEGF, VEGFR, MET, and AXL) in the tissue by multiplex quantitative immunofluorescence (MQIF).

IV. To correlate markers of immune activation and expansion of immune cell subsets and cytokines with clinical outcomes.

V. To assess the treatment effects on latent HIV reservoir. VI. To investigate the dynamic changes of immune checkpoints, angiogenesis markers, and infiltrating immune cells among subjects with available pre- and post-treatment biopsy samples (including subjects with Kaposi sarcoma [KS]).

OUTLINE

Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-28 and nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 28 days for up to 1 year or 1 year after a partial response is achieved, or 6 months after a complete response is achieved in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 16 weeks.

Details
Condition HIV infection, Immunodeficiency, Metastatic Melanoma, Advanced Solid Tumor, Recurrent Prostate Carcinoma, Recurrent Prostate Cancer, Metastatic Renal Cell Carcinoma, Metastatic Malignant Solid Neoplasm, Recurrent Ovarian Carcinoma, Metastatic Hepatocellular Carcinoma, Advanced Malignant Solid Neoplasm, Recurrent Renal Cell Carcinoma, Recurrent Malignant Solid Neoplasm, Recurrent Melanoma, Stage IV Melanoma, Stage IV Ovarian Cancer, Recurrent Head and Neck Carcinoma, Metastatic Prostate Cancer, Metastatic Prostate Carcinoma, Prostate Cancer Metastatic, Recurrent Head and Neck Cancer, Advanced Melanoma, Advanced Head and Neck Carcinoma, Recurrent Small Cell Lung Cancer, Recurrent Hepatocellular Carcinoma, Advanced Hepatocellular Carcinoma, Recurrent Ovarian Cancer, Recurrent Kaposi Sarcoma, Metastatic Urothelial Carcinoma, Metastatic Head and Neck Carcinoma, Advanced Renal Cell Carcinoma, Metastatic Solid Tumor, Primary Immunodeficiency Disorders, Stage III Hepatocellular Carcinoma AJCC v8, Stage IIIA Hepatocellular Carcinoma AJCC v8, Stage IV Hepatocellular Carcinoma AJCC v8, Stage IVA Hepatocellular Carcinoma AJCC v8, Stage IVB Hepatocellular Carcinoma AJCC v8, Advanced Urothelial Cancer, Stage III Ovarian Cancer AJCC v8, Stage IIIA Ovarian Cancer AJCC v8, Stage IIIB Ovarian Cancer AJCC v8, Stage IIIC Ovarian Cancer AJCC v8, Stage IV Ovarian Cancer AJCC v8, Stage IVA Ovarian Cancer AJCC v8, Stage IVB Ovarian Cancer AJCC v8, Stage III Renal Cell Cancer AJCC v8, Stage IVB Prostate Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8, Anatomic Stage IIIB Breast Cancer AJCC v8, Anatomic Stage IIIC Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Prognostic Stage III Breast Cancer AJCC v8, Prognostic Stage IIIA Breast Cancer AJCC v8, Prognostic Stage IIIB Breast Cancer AJCC v8, Prognostic Stage IIIC Breast Cancer AJCC v8, Prognostic Stage IV Breast Cancer AJCC v8, Stage III Prostate Cancer AJCC v8, Stage IIIA Prostate Cancer AJCC v8, Stage IIIB Prostate Cancer AJCC v8, Stage IIIC Prostate Cancer AJCC v8, Stage IV Prostate Cancer AJCC v8, Stage IVA Prostate Cancer AJCC v8, Metastatic Kidney Cancer, Clinical Stage III Cutaneous Melanoma AJCC v8, Pathologic Stage III Cutaneous Melanoma AJCC v8, Pathologic Stage IIIA Cutaneous Melanoma AJCC v8, Pathologic Stage IIIB Cutaneous Melanoma AJCC v8, Pathologic Stage IIIC Cutaneous Melanoma AJCC v8, Pathologic Stage IIID Cutaneous Melanoma AJCC v8, Stage IV Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8, Stage III Lung Cancer AJCC v8, Stage IIIA Lung Cancer AJCC v8, Stage IIIB Lung Cancer AJCC v8, Stage IIIC Lung Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8, Advanced Malignant Solid Tumor, Clinical Stage IV Cutaneous Melanoma AJCC v8, Pathologic Stage IV Cutaneous Melanoma AJCC v8, Recurrent Thyroid Gland Medullary Carcinoma, Recurrent Lung Small Cell Carcinoma, HIV Infections, Stage IV Ovarian Carcinoma, Stage IIIA1 Ovarian Cancer AJCC v8, Stage IIIA2 Ovarian Cancer AJCC v8, Stage IIIB Hepatocellular Carcinoma AJCC v8, Advanced Urothelial Carcinoma, Metastatic Head and Neck Cancer, Metastatic Ovarian Carcinoma, Refractory Differentiated Thyroid Gland Carcinoma, Advanced Prostate Carcinoma, Metastatic Lung Small Cell Carcinoma, Triple Negative Breast Carcinoma, Advanced Ovarian Carcinoma, Advanced Thyroid Gland Medullary Carcinoma, Stage III Thyroid Gland Medullary Carcinoma AJCC v8, Stage IV Thyroid Gland Medullary Carcinoma AJCC v8, Stage IVA Thyroid Gland Medullary Carcinoma AJCC v8, Stage IVB Thyroid Gland Medullary Carcinoma AJCC v8, Stage IVC Thyroid Gland Medullary Carcinoma AJCC v8, recurrent urothelial carcinoma, human immunodeficiency virus, hiv disease, advanced head and neck cancer, metastatic malignant solid tumor, Stage IV Differentiated Thyroid Gland Carcinoma AJCC v8, Stage IVA Differentiated Thyroid Gland Carcinoma AJCC v8, Stage IVB Differentiated Thyroid Gland Carcinoma AJCC v8, Advanced Differentiated Thyroid Gland Carcinoma, Advanced Kaposi Sarcoma, Advanced Lung Non-Small Cell Carcinoma, Advanced Lung Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Differentiated Thyroid Gland Carcinoma, Metastatic Kaposi Sarcoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Thyroid Gland Medullary Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Differentiated Thyroid Gland Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Stage III Differentiated Thyroid Gland Carcinoma AJCC v8, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Castration-Resistant Prostate Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Triple-Negative Breast Carcinoma
Treatment Nivolumab, Cabozantinib S-malate
Clinical Study IdentifierNCT04514484
SponsorNational Cancer Institute (NCI)
Last Modified on24 October 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Age >= 18 years. Children are excluded from this study, but will be eligible for future pediatric trials
For the six-patient safety cohort, subjects must have histologically or cytologically confirmed advanced solid tumors that are metastatic or recurrent, and require palliative systemic treatment, for which there are either Food and Drug Administration (FDA) approved indications for XL184 (cabozantinib) or nivolumab or have at least phase 2 data clearly indicating activity (such as renal cell carcinoma [RCC], hepatocellular carcinoma [HCC], medullary thyroid carcinoma [MTC], melanoma, non-small cell lung cancer [NSCLC], head and neck cancer, urothelial carcinoma, small cell lung cancer [SCLC], radioiodine-refractory differentiated thyroid cancer, ovarian cancer, castration-resistant prostate carcinoma [CRPC], and triple-negative breast cancer [TNBC]). Subjects must have progressed, or are intolerant, or decline systemic therapy associated with clinically significant survival benefit if checkpoint blockade is not an approved or accepted treatment. The expansion cohort is limited to subjects with KS. Histologic, cytologic, and pathologic confirmation of KS is required
Any number of prior cancer therapies will be permitted, including treatment naive subjects. (Note: For KS, treatment naive asymptomatic subjects will be permitted. But treatment naive KS subjects with visceral symptomatic disease or complicated KS HHV 8 disease including Castleman's disease will be excluded and should receive front-line standard of care)
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (Karnofsky >= 80%)
Subjects with tumors other than KS must have evaluable disease
Absolute neutrophil count >= 1,000/mcL
Platelets >= 75,000/mcL
Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (If, however, the participant has Gilbert's disease or unconjugated hyperbilirubinemia that is considered to be secondary to antiretroviral therapy, then the total bilirubin must be =< 3 x ULN)
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
Creatinine =< 1.5 institutional ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula)
Hemoglobin >= 9 g/dL
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
CD4 count >= 50/mcL
Subjects must have known HIV infection as below: Serologic documentation of HIV infection at any time prior to study entry, as evidenced by positive enzyme-linked immunosorbent assay (ELISA), positive Western blot, or any other federally approved licensed HIV test. Alternatively, this documentation may include a record that another physician has documented that the participant has HIV infection based on prior ELISA and Western blot, or other approved diagnostic tests. Subjects must receive appropriate care and treatment for HIV infection. An eligible patient should be on anti-retroviral therapy (ART) that is not strongly CYP3A4 inhibiting or otherwise prohibited by the protocol (e.g. drug-drug interactions) or the patient must be converted to one of these regimens before starting investigational therapy in order to avoid dose modulation of cabozantinib
Life expectancy of >= 12 weeks
For subjects with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
Subjects with a history of hepatitis C virus (HCV) infection must have been treated and cured. For subjects with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
The effects of nivolumab and XL184 (cabozantinib) 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 investigational drug. WOCBP must have a negative serum or urine pregnancy test within 72 hours prior to the start of receiving the first dose of the study medication. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab 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 investigational product. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception
Women of childbearing potential (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 less than 40 mIU/mL
Ability to understand and the willingness to sign a written informed consent document. Subjects with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible

Exclusion Criteria

For the safety run-in cohort, subjects who have received prior XL184 (cabozantinib), PD-1/PD-L1 inhibitor, or VEGFR inhibitor are ineligible. Prior treatment with these agents is allowed for the expansion KS cohort
Subjects on potent CYP3A4-inhibiting agents are ineligible, such as
Antiretroviral: ritonavir, cobicistat, indinavir, atazanavir, delavirdine
Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin
Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole, posaconazole
Antidepressants: nefazodone
Antidiuretic: conivaptan
Gastrointestinal (GI): cimetidine, aprepitant
Hepatitis C: boceprevir, telaprevir
Miscellaneous: Seville oranges, grapefruit, or grapefruit juice and/or pummelos, star fruit, exotic citrus fruits, or grapefruit hybrids Of note, to meet the eligibility requirement, subjects are allowed to convert their antiretroviral medications to one of the regimens not including potent CYP3A4-inhibiting agents, when the subjects have progressed, are intolerant, or decline the standard systemic therapy for their advanced tumors
Subjects must receive appropriate care and treatment for HIV infection
Subjects who have had cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment, or those who have not recovered from adverse events (AEs) due to agents administered more than 4 weeks earlier
including antiretroviral medications, when clinically indicated (including no
The subject has received radiation therapy
To the thoracic cavity, abdomen, or pelvis within 4 weeks before the first dose of study treatment, or has ongoing complications, or is without complete recovery and healing from prior radiation therapy
ART) and should be under the care of a physician experienced in HIV
To bone or brain metastases within 14 days before the first dose of study treatment
management. Subjects will be eligible provided there is no intention to
initiate therapy or the regimen has been stable for at least 4 weeks with no
To any other site(s) within 21 days before the first dose of study treatment
intention to change the regimen within 8 weeks following study entry
Subjects who are receiving any other investigational agents
To enroll in the study, the participants should be on the protocol accepted
Subjects must be either off corticosteroids, or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent) for at least 2 weeks prior to enrollment. Inhaled or topical steroids are permitted in the absence of active autoimmune disease
ART as long as they are receiving XL184 (cabozantinib)
History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab or XL184 (cabozantinib)
The subject has prothrombin time (PT)/ international normalized ratio (INR) or partial thromboplastin time (PTT) test >= 1.3 x the laboratory ULN within 7 days before the first dose of study treatment
The subject has a primary brain tumor, active brain metastases or epidural disease. Subjects with brain metastases previously treated with whole brain radiation or radiosurgery or participants with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible. Subjects with treated brain metastasis should not take enzyme-inducing anticonvulsive therapies (EIACDs) within 2 weeks of registration, though non-enzyme inducing anticonvulsive drugs such as levetiracetam are allowed. Neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment. Baseline brain imaging with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans for participants with known brain metastases is required to confirm eligibility. Subjects with untreated central nervous system (CNS) metastases are eligible if they are not symptomatic and the lesions are less than 1 cm in size. CNS metastases should be stable for at least 4 weeks, neurologically asymptomatic and without corticosteroid treatment at time of first dose of study treatment
Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following
Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH)
Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor
The subject has experienced any of the following
Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment
Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
The subject has radiographic evidence of cavitating pulmonary lesion(s)
The subject has tumor in contact with, invading, or encasing any major blood vessels
The subject has evidence of tumor invading the 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 treatment
The subject has uncontrolled and significant cardiovascular disorders
Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening
Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment
The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before treatment
Note: If initial QTcF is found to be > 500 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is =< 500 ms, the subject meets eligibility in this regard
Any of the following within 6 months before the first dose of study treatment
Unstable angina pectoris
Clinically-significant cardiac arrhythmias
Stroke
Myocardial infarction
Subjects with a venous filter (e.g. vena cava filter) are not eligible
Thromboembolic event
The subject has uncontrolled and significant disorders particularly those associated with a high risk of perforation or fistula formation including
Any of the following within 28 days before the first dose of study treatment
Active and symptomatic peptic ulcer disease
Evidence of active or acute diverticulitis, intra-abdominal abscess, GI obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study
Any of following within 6 months before the first dose of study treatment
Abdominal fistula
Gastrointestinal perforation
Bowel obstruction or gastric outlet obstruction intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 6 months before
Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy
Subjects with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded. These include but are not limited to subjects with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and subjects 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. Subjects with vitiligo, endocrine deficiencies including thyroiditi
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