| Eligibility |
Inclusion Criteria:
- Patients must have histologically or cytologically confirmed metastatic STS,
specifically undifferentiated pleomorphic sarcoma (UPS), extraskeletal myxoid
chondrosarcoma (EMC), liposarcoma (LPS) or non-uterine leiomyosarcoma (LMS) that are
locally advanced and surgically unresectable
- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest
x-ray or as >= 10 mm (>= 1 cm) with CT scan, MRI, or calipers by clinical exam.
Disease will be measured by RECISTv1.1
- Patients with prior treatment with MET or VEGFR inhibitors are allowed. However, prior
cabozantinib-treated patients will not be allowed. Prior ipilimumab in combination
with nivolumab-treated patients will not be allowed
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Absolute neutrophil count >= 1,000/mcL
- Platelets >= 75,000/mcL
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional ULN
- Creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 50
mL/min/1.73 m^2
- Serum albumin >= 2.8g/dL
- Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis
- Urine protein/creatinine ratio (UPCR) =< 1
- For patients with evidence of chronic hepatitis B virus (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 undetectable HCV viral load 12 or more weeks after treatment completion. For
patients with HCV infection who are currently on treatment, they are eligible if they
have an undetectable HCV viral load
- Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression >= 1
month after treatment of the brain metastases. 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 2 cycles of therapy
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class 2B or better
- Patients must be willing to provide blood specimens and undergo biopsies for research
purposes
- Patients with baseline blood pressure (BP) lower than 140 mmHg (systolic) and 90 mmHg
(diastolic). Patients on > 2 anti-hypertensive agents will be excluded
- Human immunodeficiency virus (HIV)-infected patients on effective combination
antiretroviral therapy are eligible as long as HIV is well-controlled and there is
undetectable viral load within 6 months. For these patients, an HIV viral load test
must be completed within 28 days prior to enrollment
- The effects of nivolumab, ipilimumab, and cabozantinib on the developing human fetus
are unknown. For this reason and because other therapeutic agents used in this trial
are known to be teratogenic, 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
(defined as any female who has experienced menarche and who has not undergone surgical
sterilization [hysterectomy or bilateral oophorectomy] or who is not postmenopausal)
should use an adequate method to avoid pregnancy for 5 months after the last dose of
investigational drug. 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]) at the time of enrollment and within 8 days prior to
each cycle. Women must not be breastfeeding
- Men who are sexually active with women of child-bearing potential (WOCBP) must use any
contraceptive method with a failure rate of less than 1% per year. Men receiving
cabozantinib and who are sexually active with WOCBP will be instructed to adhere to
contraception for a period of 5 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
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia, stable
hyperthyroidism on replacement therapy, type-1 diabetes, well-controlled insulin, and
non-clinically significant toxicities at the discretion of the study Principal
Investigator
- Patients who are receiving any other investigational agents
- Eligibility of subjects receiving any medications or substances known to affect or
with the potential to affect the activity of cabozantinib will be determined following
review of their cases by the Principal Investigator. Patients who are taking
enzyme-inducing anticonvulsant agents are not eligible
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to cabozantinib, nivolumab, or ipilimumab
- Patients receiving any medications or substances that are strong inhibitors or
inducers of CYP3A4 are ineligible. Strong CYP3A4 inducers (e.g., phenytoin,
carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's Wort)
are not allowed for this study. Because the lists of these agents are constantly
changing, frequently updated lists available at
http://medicine.iupui.edu/clinpharm/ddis/table.asp or other reliable resources will be
consulted. Patients who need to come off CYP3A4 inhibitors/inducers should adhere to a
washout period of at least 5 times the half-life of the CYP3A4 inhibitors and 14 days
of CYP3A4 inducers
- Patients with any other significant condition(s) that would make this protocol
unreasonably hazardous are ineligible. Patients with uncontrolled intercurrent illness
or clinical evidence of an active infection at the time of enrollment are ineligible
- Pregnant women are excluded from this study because cabozantinib is a receptor kinase
inhibitor agent 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 cabozantinib in combination with nivolumab and
ipilimumab, breastfeeding should be discontinued if the mother is treated with
cabozantinib. These potential risks may also apply to other immunotherapeutic agents
(ipilimumab and nivolumab) used in this study
- Patients that require concomitant treatment, in therapeutic doses, with anticoagulants
such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa
inhibitors, or antiplatelet agents (e.g., clopidogrel). Low dose aspirin (=< 81
mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight
heparin (LMWH) are permitted. (Please note that there may be cases in which patients
on study require anticoagulation for deep vein thrombosis/pulmonary embolism [DVT/PE]
management; this does not necessitate taking the patient off study)
- Patients with any of the following within 12 weeks prior to the first dose of
cabozantinib: gastrointestinal bleeding, hemoptysis or pulmonary hemorrhage,
radiographic evidence of cavitating pulmonary lesion(s), evidence of tumor invasion of
the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum, or
anus), or any evidence of endotracheal or endobronchial tumor or encasement of any
major blood vessels
- The patient is unable to swallow tablets
- The patient has a corrected QT interval calculated by the Fridericia formula (QTcF) >=
470 ms within 28 days before enrollment
- Patients with a requirement for steroid or immunosuppressive treatment should be
excluded if they have a condition requiring systemic treatment with either
corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive
medications within 14 days of study drug administration. Inhaled or topical steroids
and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in
the absence of active autoimmune disease
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