Inclusion Criteria:
- Histologically confirmed cutaneous or visceral angiosarcoma, where curative treatment
is either not possible or curative modality therapy is declined by the subject. Note:
If a subject declines curative modality therapy, the reason must be documented (e.g.
excessive morbidity to necessary surgery)
- Note: Radiation induced angiosarcomas are permitted
- All local diagnostic slides AND 5 x 4-6 micron unstained slides from
diagnostic tumor tissue should be available for retrospective central
pathology review
- Must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST)
version (v)1.1. Per RECIST v1.1, clinical lesions will only be considered measurable
when they are superficial and P10 mm diameter as assessed using calipers or ruler
(e.g. skin nodules). For the case of skin lesions, documentation by color photography
including a ruler to estimate the size of the lesion is required. When lesions can be
evaluated by both clinical exam and imagining, imaging evaluation should be undertaken
since it is more objective and may also be reviewed at the end of the study. The same
method of measurement should be used throughout the study, preferably performed by the
same investigator. Areas previously radiated must have demonstrated disease
progression at some point over the past 6 months and growth must be subsequent to the
last line of anti-cancer directed therapy (e.g. chemotherapy, radiation therapy,
surgery)
- 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 pregnancy test
done =< 3 days prior to registration is required
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Prior Treatment
- Patient must have completed all prior treatments (including investigational) >=
28 days prior to cycle 1 day 1
- Exception: prostate patients who are allowed to concurrently receive
androgen suppression therapy
- Exception: Targeted small molecule chemotherapy or radiation must be
completed >= 14 days of day 1 of study treatment. For targeted
chemotherapies, prior therapies must be completed prior to registration and
final dose must have occurred > 5 half-lives prior to cycle 1 day 1
- There is no limit to overall number of prior lines of therapy
- No prior PD-1 inhibitor or PD-L1 inhibitor therapy is permitted
- No prior administration of VEGF TKI therapy is permitted
- Recovery to baseline or' =< grade 1 CTCAE version 5.0 from toxicity related to
any prior treatment, unless adverse events are clinically nonsignificant and/or
stable on supportive therapy, with the exception of fatigue (which should be =<
grade 2) or alopecia
- Taxane Naive Patients Only: No prior exposure to taxane therapy of any duration for
angiosarcoma
- Taxane Pre-treated Patients Only: Prior taxane therapy is allowed at any point prior
to registration as long as it is >= 28 days prior to cycle 1 day 1
- No major surgery (except the diagnostic biopsy) =< 28 days of study registration.
Procedures such as thoracentesis, paracentesis, percutaneous biopsy, Lasik eye surgery
are not considered major surgery. Subjects with clinically relevant ongoing
complications from prior surgery are not eligible
- Absolute neutrophil count (ANC) >= 1,000/mm^3
- Platelet count >= 100,000/mm^3
- Hemoglobin >= 9.0 g/dL
- Calculated (Calc.) creatinine clearance >= 30 mL/min (per Cockcroft-Gault)
- Total bilirubin =< 1.5 x upper limit of normal (ULN)
- For patients with documented/suspected Gilbert's disease, bilirubin =< 3 x ULN
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit
of normal (ULN)
- For patients with significant hepatic metastases, ALT and AST =< 5 x ULN. No
clinically active or chronic liver disease resulting in moderate/severe hepatic
impairment (Child-Pugh class B or C), ascites, coagulopathy or bleeding due to
liver dysfunction
- Urine protein:creatinine (UPC) ratio < 1 or urine protein =< 1+
- No uncontrolled central nervous system (CNS) metastases. Patients with history of CNS
metastasis will be allowed as long as the metastatic sites were adequately treated as
demonstrated by clinical and radiographic improvement, and the patient has recovered
from the intervention (no residual adverse events > CTCAE grade 1), and the patient
has remained without recurrence of new or worsening CNS symptoms for a period of 28
days prior to registration. Treated CNS metastasis (mets) should have no ongoing
requirement for steroids, and no evidence of hemorrhage after treatment for at least
28 days prior to registration
- No uncontrolled intercurrent illness that would put the patient at undue risk by
participation in the study, in the opinion of the investigator
- No history of syncope of cardiovascular etiology, uncontrolled cardiac arrhythmia,
History of Mobitz II second degree or third degree heart block without a permanent
pacemaker in place, myocardial ischemia or infarction, severe or unstable angina, New
York Heart Association (NYHA) class II to IV heart failure, or stroke/transient
ischemic attack (TIA) within the past 3 months
- No thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 1
month before randomization. Subjects with a diagnosis of incidental, subsegmental
pulmonary embolism (PE) or deep vein thrombosis (DVT) within 6 months are allowed if
stable, asymptomatic, and treated with low molecular weight heparin (LMWH) for at
least 2 weeks before first dose. Iatrogenic arterial embolization procedures such as
tumor arterial embolization or splenic artery embolization are allowed
- Patients with a requirement for steroid treatment or other immunosuppressive
treatment: Patients 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. Patients are permitted to
use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids
(with minimal systemic absorption). A brief 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 contact allergen) is permitted
- Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,
residual hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger (precipitating event)
- Active autoimmune disease requiring systemic treatment (i.e. disease modifying agents,
corticosteroids, or immunosuppressive drugs) within the past 2 years. These include
but are not limited to patients 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), rheumatoid arthritis, connective tissue diseases, scleroderma, inflammatory
bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and 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
- Note: Patients are permitted to enroll if they have vitiligo; type I diabetes
mellitus; hypothyroidism, pituitary or adrenal insufficiency requiring only
hormone replacement; psoriasis not requiring systemic treatment, or conditions
not expected to recur in the absence of an external trigger (precipitating event)
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- No planned palliative procedures for alleviation of pain such as radiation therapy or
surgery
- No untreated or impending spinal cord compression or evidence of spinal metastases
with a risk of impending fracture or spinal cord compression
- No known or suspected contraindications or hypersensitivity to paclitaxel,
cabozantinib or nivolumab or to any of the excipients
- Disorders associated with a high risk of perforation or fistula formation: active
inflammatory bowel disease, active diverticulitis, active cholecystitis, active
symptomatic cholangitis or active appendicitis, active acute pancreatitis or active
acute obstruction of the pancreatic or biliary duct, or active gastric outlet
obstruction; abdominal fistula, gastrointestinal perforation, bowel obstruction, or
intra-abdominal abscess within 6 months before randomization. Note: Complete healing
of an intra-abdominal abscess must be confirmed before randomization
- No clinically significant hematuria, hematemesis, or hemoptysis, or other history of
significant bleeding (e.g., pulmonary hemorrhage) within 3 months before randomization
- No lesions invading major pulmonary blood vessels
- No other clinically significant disorders: serious non-healing wound or ulcer;
malabsorption syndrome; uncompensated/symptomatic hypothyroidism; requirements for
hemodialysis or peritoneal dialysis; history of solid organ transplantation
- Chronic concomitant treatment with strong inhibitors and inducers of CYP3A4 is not
allowed on this study. Patients on strong CYP3A4 inhibitors and inducers must
discontinue the drug 7 days and 14 days, respectively prior to registration on the
study
- Taxane Naive Patients Only: No clinically significant neuropathy (grade >= 2 per NCI
CTCAE v5.0)
- Taxane Pre-treated only:
- Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI),
or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis,
pulmonary embolism) within 6 months before first dose. Subjects with a diagnosis
of DVT within 6 months are allowed if stable and treated with LMWH for at least 2
weeks before first dose
- No history of clinically significant coagulopathy. 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
- No uncontrolled hypertension, defined as systolic blood pressure of > 140 mmHg or
diastolic pressure > 90 mmHg on anti-hypertensive medications
- No known or suspected gastrointestinal disorder affecting absorption of oral
medications (for patients getting cabozantinib)
- No clinical, laboratory or radiographic evidence of an active bacterial, fungal, or
viral infection requiring treatment at the time of registration. No concurrent use of
parenteral (IV) antibiotics is permitted. Oral antibiotics administered for a defined
course with expectation of resolution of infection are permitted at the discretion of
the investigator
- No use of ongoing systemic steroid therapy within 7 days prior to study registration.
Dose equivalence of prednisone 10mg daily or less is permitted
- Taxane Pre-treated only:
- No current use of aspirin (> 81 mg/day), or any other antiplatelet agents
- Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct
thrombin inhibitors, and factor Xa inhibitors) or platelet inhibitors (e.g.,
clopidogrel) is not permitted. Low-dose (prophylactic) low molecular weight
heparins (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH is
allowed in subjects with no known brain metastases, no clinically significant
hemorrhage, or no complications from a thromboembolic event on the
anticoagulation regimen, and who have been on a stable dose of LMWH for at least
2 weeks before first dose
- Patients must be able to speak and comprehend English or Spanish in order to complete
the mandatory patient-completed measures
- Re-Registration Eligibility Criteria (upon progression on Arm 2 only): 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 pregnancy test
done =< 3 days prior to re-registration is required
- Re-Registration Eligibility Criteria (upon progression on Arm 2 only): ECOG
performance status 0-1
- Re-Registration Eligibility Criteria (upon progression on Arm 2 only): Prior Treatment
- Patient must have completed all prior treatments (including investigational Arm 2
paclitaxel) >= 28 days prior to cycle 1 day 1
- Exception: prostate patients who are allowed to concurrently receive
androgen suppression therapy
- Note: Re-registration is only permitted after progression on Arm 2
- No prior PD-1 inhibitor or PD-L1 inhibitor therapy is permitted
- Recovery to baseline or =< grade 1 CTCAE version 5.0 from toxicity related to any
prior treatment, unless adverse events are clinically nonsignificant and/or
stable on supportive therapy, with the exception of fatigue (which should be =<
grade 2) or alopecia
- Re-Registration Eligibility Criteria (upon progression on Arm 2 only): No major
surgery (except the diagnostic biopsy) =< 28 days of study re-registration. Procedures
such as thoracentesis, paracentesis, percutaneous biopsy, Lasik eye surgery are not
considered major surgery. Subjects with clinically relevant ongoing complications from
prior surgery are not eligible
- Re-Registration Eligibility Criteria (upon progression on Arm 2 only): Absolute
neutrophil count (ANC) >= 1,000/mm^3
- Re-Registration Eligibility Criteria (upon progression on Arm 2 only): Platelet count
>= 100,000/mm^3
- Re-Registration Eligibility Criteria (upon progression on Arm 2 only): Hemoglobin >=
9.0 g/dL
- Re-Registration Eligibility Criteria (upon progression on Arm 2 only): Calc.
creatinine clearance >= 30 mL/min (per Cockcroft-Gault)
- Re-Registration Eligibility Criteria (upon progression on Arm 2 only): Total bilirubin
=< 1.5 x upper limit of normal (ULN)
- For patients with documented/suspected Gilbert's disease, bilirubin =< 3 x ULN
- Re-Registration Eligibility Criteria (upon progression on Arm 2 only): AST/ALT =< 2.5
x upper limit of normal (ULN)
- For patients with significant hepatic metastases, ALT and AST =< 5 x ULN. No
clinically active or chronic liver disease resulting in moderate/severe hepatic
impairment (Child-Pugh class B or C), ascites, coagulopathy or bleeding due to
liver dysfunction
- Re-Registration Eligibility Criteria (upon progression on Arm 2 only): UPC ratio < 1
or urine p
