- Histologically or cytologically confirmed metastatic or unresectable soft tissue
- Measurable disease defined as lesions that can be accurately measured in at least one
dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by
chest x-ray, or ≥ 10 mm with calipers by clinical exam.
- Refractory to at least one and no more than two lines of therapy.
- At least 18 years of age.
- ECOG performance status ≤ 1
- Normal bone marrow and organ function as defined below:
- Absolute neutrophil count ≥ 1,500/mm3 without granulocyte colony-stimulating
- White blood cell count ≥ 2,000/mm3
- Platelets ≥ 100,000/mm3 without transfusion
- Hemoglobin ≥ 9.0 g/dL
- Total bilirubin ≤ 1.5 x IULN (for subjects with Gilbert's disease, ≤ 3.0 x IULN)
- AST(SGOT), ALT(SGPT), and alkaline phosphatase (ALP) ≤ 3.0 x IULN; ALP ≤ 5.0 x
IULN with documented bone metastases
- Serum albumin ≥ 2.8 g/dl.
- Serum creatinine ≤ 1.5x IULN or calculated creatinine clearance ≥ 40 mL/min by
- Urine protein/creatinine ration (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol)
- PT/INR or PTT < 1.3 x IULN (within 7 days before first dose of study treatment)
- Corrected QT interval calculated by the Fridericia formula (QTcF) ≤ 500 ms (by ECG
within 28 days before the first dose of study treatment).
- Recover to baseline or ≤ grade 1 from toxicities related to any prior treatments,
unless AE(s) are clinically non-significant and/or stable on supportive therapy.
- The effects of cabozantinib on the developing human fetus are unknown. For this
reason, women of childbearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control, abstinence) prior to study
entry, for the duration of study participation, and for 5 months after the last dose
of study treatment. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she must inform her treating physician immediately. Men
treated or enrolled on this protocol must also agree to use adequate contraception
prior to the study, for the duration of the study, and for at least 7 months after the
last dose of study treatment.
- Ability to understand and willingness to sign an IRB approved written informed consent
document (or that of legally authorized representative, if applicable).
- Translocation-driven sarcoma except for ASPS
- Previous treatment with cabozantinib or a PD-1 inhibitor, PD-L1 inhibitor, or CTLA-4
- A history of other malignancy with the exception of malignancies for which all
treatment was completed at least 2 years before registration and the patient has no
evidence of disease. Exceptions include basal cell or squamous cell carcinoma of the
skin which were treated with local resection only or carcinoma in situ of the cervix,
or other tumors discussed with the study PI.
- Currently receiving any other investigational agents.
- Known brain metastases. Patients with known brain metastases must be excluded from
this clinical trial because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other adverse events.
- Receipt of any type of small molecule kinase inhibitor (including investigational
kinase inhibitor) within 2 weeks before first dose of study treatment.
- Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy
(including investigational) within 4 weeks before 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.
- Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy
within 4 weeks before first dose of study treatment. Systemic treatment with
radionuclides within 6 weeks before the first dose of study treatment. Subjects with
clinically relevant ongoing complications from prior radiation therapy are not
- A history of allergic reactions attributed to compounds of similar chemical or
biologic composition to cabozantinib, nivolumab, ipilimumab, or other agents used in
- Inability to swallow tablets.
- The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
- Cardiovascular disorders:
- Congestive heart failure New York Heart Association Class 3 or 4, unstable
angina pectoris, serious cardiac arrhythmias.
- Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm
Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive
- 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 of study
- Subjects with a diagnosis of incidental, subsegmental PE or DVT within
6 months are allowed if stable, asymptomatic, and treated with
anticoagulation for at least 1 week before first dose of study
- Gastrointestinal (GI) disorders including those associated with a high risk of
perforation or fistula formation:
- The subject has evidence of tumor invading the GI tract, active peptic ulcer
disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis,
cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis,
acute obstruction of the pancreatic duct or common bile duct, or gastric
- Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal
abscess within 6 months before first dose.
- Note: Complete healing of an intra-abdominal abscess must be confirmed
before first dose.
- Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon
(2.5 ml) of red blood, or other history of significant bleeding (eg, pulmonary
hemorrhage) within 12 weeks before first dose.
- Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
- Lesions invading or encasing any major blood vessels.
- Other clinically significant disorders that would preclude safe study
- Serious non-healing wound/ulcer/bone fracture.
- Uncompensated/symptomatic hypothyroidism.
- Moderate to severe hepatic impairment (Child-Pugh B or C)
- Any active, known, or suspected autoimmune disease Note: subjects with type I diabetes
mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as
vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not
expected to recur in the absence of an external trigger are permitted to enroll.
- Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily
prednisone equivalent) or other immunosuppressive medications within 14 days of
randomization Note: inhaled, intranasal, intra-articular, or topical steroids are
permitted. Adrenal replacement steroid doses > 10 mg daily prednisone equivalent are
permitted in the absence of active autoimmune disease. Transient short-term use of
systemic corticosteroids for allergic conditions (e.g. contrast allergy) is also
- Active infection requiring systemic treatment. Acute or chronic hepatitis B or C
infection, known human immunodeficiency virus (HIV) or acquired immunodeficiency
syndrome (AIDS)-related illness, or known positive test for tuberculosis infection
- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced
pneumonitis, or evidence of active pneumonitis on screening chest CT scan
- Malabsorption syndrome
- Requirement for hemodialysis or peritoneal dialysis
- History of solid organ or allogeneic stem cell transplant.
- Major surgery (e.g. GI surgery removal or biopsy of brain metastasis) within 8 weeks
before first dose of study treatment. Complete wound healing from major surgery must
have occurred 1 month before first dose and from minor surgery (e.g., simple excision,
tooth extraction) at least 10 days before first dose. Patients with clinically
relevant ongoing complications from prior surgery are not eligible.
- Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
pregnancy test within 15 days of study entry. Women of childbearing potential are
defined as premenopausal females capable of becoming pregnant (i.e., females who have
had any evidence of menses in the past 12 months, with the exception of those who had
prior hysterectomy). However, women who have been amenorrheic for 12 or more months
are still considered to be of childbearing potential if the amenorrhea is possibly due
to prior chemotherapy, antiestrogens, low body weight, ovarian suppression, or other
- Administration of a live, attenuated vaccine within 30 days prior to randomization.