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

Running, not enrolling · Phase 1

Conditions studied: Advanced Differentiated Thyroid Gland Carcinoma, Advanced Head and Neck Carcinoma, Advanced Hepatocellular Carcinoma, Advanced Kaposi Sarcoma, Advanced Lung Non-Small Cell Carcinoma, Advanced Lung Small Cell Carcinoma, Advanced Malignant Solid Neoplasm, Advanced Melanoma, Advanced Ovarian Carcinoma, Advanced Prostate Carcinoma, Advanced Renal Cell Carcinoma, Advanced Thyroid Gland Medullary Carcinoma, Advanced Triple-Negative Breast Carcinoma, Advanced Urothelial Carcinoma, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Castration-Resistant Prostate Carcinoma, Clinical Stage III Cutaneous Melanoma AJCC v8, Clinical Stage IV Cutaneous Melanoma AJCC v8, HIV Infection, Metastatic Differentiated Thyroid Gland Carcinoma, Metastatic Head and Neck Carcinoma, Metastatic Hepatocellular Carcinoma, Metastatic Kaposi Sarcoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Lung Small Cell Carcinoma, Metastatic Malignant Solid Neoplasm, Metastatic Melanoma, Metastatic Ovarian Carcinoma, Metastatic Prostate Carcinoma, Metastatic Renal Cell Carcinoma, Metastatic Thyroid Gland Medullary Carcinoma, Metastatic Triple-Negative Breast Carcinoma, Metastatic Urothelial Carcinoma, Recurrent Differentiated Thyroid Gland Carcinoma, Recurrent Head and Neck Carcinoma, Recurrent Hepatocellular Carcinoma, Recurrent Kaposi Sarcoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Lung Small Cell Carcinoma, Recurrent Malignant Solid Neoplasm, Recurrent Melanoma, Recurrent Ovarian Carcinoma, Recurrent Prostate Carcinoma, Recurrent Renal Cell Carcinoma, Recurrent Thyroid Gland Medullary Carcinoma, Recurrent Triple-Negative Breast Carcinoma, Recurrent Urothelial Carcinoma, Refractory Differentiated Thyroid Gland Carcinoma, Stage III Differentiated Thyroid Gland Carcinoma AJCC v8, Stage III Hepatocellular Carcinoma AJCC v8, Stage III Lung Cancer AJCC v8, Stage III Ovarian Cancer AJCC v8, Stage III Prostate Cancer AJCC v8, Stage III Renal Cell Cancer AJCC v8, Stage III Thyroid Gland Medullary Carcinoma AJCC v8, Stage IV Differentiated Thyroid Gland Carcinoma AJCC v8, Stage IV Hepatocellular Carcinoma AJCC v8, Stage IV Lung Cancer AJCC v8, Stage IV Ovarian Cancer AJCC v8, Stage IV Prostate Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8, Stage IV Thyroid Gland Medullary Carcinoma AJCC v8

In brief

This phase I trial investigates the side effects of cabozantinib and nivolumab in treating patients with cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of 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.

Key facts

Study ID

NCT04514484

Run by

National Cancer Institute (NCI)

People needed

8

Starts

2021-11-22

Expected to finish

2027-02-06

Last updated by the study team

2026-05-28

Who can join

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

You may qualify if…

• 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
• 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 including self-cured cases. 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

You may not qualify if…

• 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, including antiretroviral medications, when clinically indicated (including no ART) and should be under the care of a physician experienced in HIV 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 intention to change the regimen within 8 weeks following study entry.
• To enroll in the study, the participants should be on the protocol accepted ART as long as they are receiving XL184 (cabozantinib)
• 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
• 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
• To bone or brain metastases within 14 days before the first dose of study treatment
• To any other site(s) within 21 days before the first dose of study treatment
• Subjects who are receiving any other investigational agents
• 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
• 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 CT or 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

Where it is running

• Northwestern University — Chicago, Illinois, United States
• Montefiore Medical Center-Einstein Campus — The Bronx, New York, United States
• University of Pittsburgh Cancer Institute (UPCI) — Pittsburgh, Pennsylvania, United States

Full record on ClinicalTrials.gov

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