| Eligibility |
Inclusion Criteria:
- Patients must have histologically documented nasopharyngeal carcinoma (NPC) regardless
of World Health Organization (WHO) classification (keratinizing squamous cell
carcinoma, non-keratinizing, or basaloid squamous cell carcinoma) and regardless of
association with Epstein-Barr virus (EBV) and/or human papillomavirus (HPV)
- Recurrent, metastatic and incurable disease treated with platinum-gemcitabine and
prior PD-1/L1 blockade (as first or second-line therapy) where immunotherapy was part
of the most recent prior line of therapy
- Patients are eligible regardless of prior smoking history, p16 immunohistochemistry
(IHC) status, PD-L1 expression status, EBV tumor status, EBV viral load at baseline,
or tumor genomic alteration status
- Patients must have at least one measurable lesion (by RECIST v1.1) which has not been
previously irradiated that can be accurately measured in at least one dimension
(longest diameter to be recorded for non-nodal lesions as >= 10 mm (>= 1 cm) (and
short axis for nodal lesions, LN >= 15 mm) with CT scan, MRI, or calipers by clinical
exam
- Patients may have had no more than 2 prior lines of prior systemic therapy for
recurrent, metastatic NPC
- No prior VEGFR targeted therapy permitted
- Age >= 18 years
- Eastern Cooperative Oncology Group Performance (ECOG) performance status 0-2
- Absolute neutrophil count (ANC) >= 1,000/mm^3
- Hemoglobin >= 9 g/dL
- Platelet count >= 100,000/mm^3
- Creatinine or creatinine clearance =< 1.5 mg/dL or >= 30 Modification of Diet in Renal
Disease (MDRD)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN); except subjects
with Gilbert syndrome who can have a total bilirubin < 3 mg/dL
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase =< 3 x
upper limit of normal (ULN)
* Up to =< 5 allowed with liver metastases
- Not pregnant and not nursing, because this study involves an investigational agent
whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn
are unknown. Therefore, for women of childbearing potential only, a negative urine or
serum pregnancy test, per institution standard, done =< 7 days prior to registration
is required.
* Pregnant women are excluded from this study because nivolumab, ipilimumab, and
cabozantinib are all Class C or D agents with the potential for teratogenic or
abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants, secondary to treatment of the mother with any of the study
agents, breastfeeding should be discontinued if the mother is treated with as part of
this study (in either arm)
- No active tumor bleeding: or radiographic evidence of major blood vessel infiltration
as judged by the treating investigator
- Prior -anti-cancer therapy is allowed: Patients need to be recovered from adverse
events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1),
with the exception of alopecia. Any life-threatening events clearly attributable to
prior immunotherapy exposure that have a high possibility of recurring should warrant
exclusion: including severe pneumonitis, grade 4 bullous dermatitis/drug reaction with
eosinophilia and systemic symptoms (DRESS), neurologic events such as autoimmune
encephalitis transverse myelitis, and/or myocarditis. Maintenance hormonal replacement
or long-term hormonal therapy exposure is permitted.
* No chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or
mitomycin C) prior to registration. Palliative (limited-field) radiation therapy is
permitted, if all of the following criteria are met:
- Repeat imaging demonstrates no new sites of bone metastases.
- The lesion being considered for palliative radiation is not a target lesion
- No patients with a prior malignancy whose natural history or treatment has the
potential to interfere with the safety or efficacy assessment of the investigational
regimen
- Brain metastases allowed: Patients with treated brain metastases are eligible if
follow-up brain imaging 4 weeks after central nervous system (CNS)-directed therapy
shows no evidence of progression. Patients with new or progressive brain metastases
(active brain metastases) or leptomeningeal disease are eligible if the treating
physician determines that immediate CNS specific treatment is not required and is
unlikely to be required during the first cycle of therapy
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months prior to registration are
eligible for this trial
- For patients with evidence of chronic hepatitis B (HBV) infection, the HBV viral load
must be undetectable on suppressive therapy, if indicated
* Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently receiving treatment, they
are eligible if they have an undetectable HCV viral load
- Solid organ or tissue transplant is allowed: - subsequent therapy with nivolumab
increases the risk of organ/tissue rejection. Patients must be instructed that it is
crucial they stay in touch with their transplant team during treatment
- No active autoimmune disease: or history of autoimmune disease that might recur, and
which may affect vital organ function or require immune suppressive treatment
including systemic corticosteroids. These include but are not limited to patients with
a history of
- Immune related neurologic disease,
- Multiple sclerosis,
- Autoimmune (demyelinating) neuropathy,
- Guillain-Barre syndrome (GBS),
- Myasthenia gravis;
- Systemic autoimmune disease such as SLE,
- Connective tissue diseases,
- Scleroderma, inflammatory bowel disease (IBD),
- Crohn's, ulcerative colitis,
- 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, endocrine deficiencies including 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 only positive serology,
such as 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
- Pneumonitis should be evaluated for the nature of the disease process, need for
treatment prior study treatment, and the risk of exacerbation with study treatment
- Able to swallow oral medication: No known medical condition causing an inability to
swallow oral formulations of agents
- No condition requiring systemic treatment with either corticosteroids (> 10 mg daily
prednisone equivalent) or other immunosuppressive medications within 14 days of study
registration. Patients are permitted the use of topical, ocular, intra-articular,
intranasal, and inhalational corticosteroids (with minimal systemic absorption).
Adrenal replacement steroid doses > 10 mg daily prednisone are permitted. A brief
(less than 3 weeks) course of corticosteroids for prophylaxis (e.g., contrast dye
allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type
hypersensitivity reaction caused by a contact allergen) is permitted
- 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) is prohibited. 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
- Concomitant use of any medications or substances that are strong inhibitors or
inducers of CYP3A4 is discouraged; if unavoidable, the dose of cabozantinib on study
should be adjusted accordingly. Any complementary medications (e.g., herbal
supplements or traditional Chinese medicines) intended to treat the disease under
study are prohibited
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