| Eligibility |
Inclusion Criteria:
1. Histologically (or cytologically) confirmed diagnosis of metastatic cutaneous
melanoma.
2. Prior therapy:
1. Must have been treated previously with an immune checkpoint inhibitor targeting
PD-1 or PD-L1.
2. Disease progression following treatment with prior anti-PD-1/PD-L1 therapy must
be confirmed at least 4 weeks after the first imaging showing disease progression
to rule out pseudoprogression.
3. Prior therapy with BRAF/MEK inhibitors (before or after anti-PD-1(L1) therapy) is
allowed but not required.
4. Patients who develop unresectable/metastatic disease while receiving or following
completion of adjuvant systemic anti-PD-1/PD-L1 therapy are eligible.
3. Recovery to baseline or = Grade 1 CTCAE v5 from toxicities related to any prior
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive
therapy.
4. Men and women, aged = 18 years
5. Measurable disease meeting the following iRECIST criteria:
1. At least 1 lesion of =1.0 cm in the longest diameter for a non-lymph node or >1.5
cm in the short-axis diameter for a lymph node metastasis that is serially
measurable according to iRECIST using computed tomography/magnetic resonance
imaging (CT/MRI).
2. Lesions that have had external beam radiotherapy must show evidence of disease
progression to qualify as a target lesion.
6. ECOG performance status = 1
7. Adequate cardiac function, as defined by:
1. Left ventricular ejection fraction (LVEF) = 50% as determined by a multigated
acquisition (MUGA) scan or echocardiogram,
2. Baseline QTc interval = 480 ms
8. Adequate organ and marrow function, based upon meeting all of the following laboratory
criteria within 14 days before first dose of study treatment:
1. Absolute neutrophil count (ANC) = 1500/µL without granulocyte colony-stimulating
factor support.
2. White blood cell count = 2500/µL.
3. Platelets = 100, 000/µL without transfusion.
4. Hemoglobin = 9 g/dL (= 90 g/L).
5. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline
phosphatase (ALP) = 3x upper limit of normal (ULN). ALP = 5x ULN with documented
bone metastases.
6. Total bilirubin < 1.5 x ULN. Note: Individuals who have a total bilirubin level
>1.5 X ULN will be allowed if their indirect bilirubin level is < 1.5 x ULN
(i.e., participants with suspected or known diagnosis of Gilbert's Syndrome)
7. Serum albumin = 2.8 g/dl.
8. (PT)/INR or partial thromboplastin time (PTT) test < 1.3x the laboratory ULN
9. Serum creatinine = 1.5x ULN or calculated creatinine clearance = 40mL/min (=
0.675mL/sec) using the Cockcroft-Gault equation:
Males: (140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72) Females: [(140 -
age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85
10. Urine protein/creatinine ratio (UPCR) = 1 mg/mg (= 113.2 mg/mmol), or 24-h urine
protein = 1 g.
9. Capable of understanding and complying with the protocol requirements and must have
signed the informed consent document.
10. Sexually active fertile subjects and their partners must agree to use medically
accepted methods of contraception (e.g., barrier methods, including male condom,
female condom, or diaphragm with spermicidal gel) during the course of the study and
for 4 months after the last dose of cabozantinib and 3 months after the last dose of
ipilimumab and 5 months after the last dose of nivolumab.
11. Participants 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 screening, within 24 hours prior to receiving the first dose of study
medication, and then every 4 weeks while on treatment.
12. Participants of child-bearing potential agree to use highly effective methods of
contraception starting with the first dose of assigned study intervention through 5
months after the last dose of study therapy. Participants of childbearing potential
are those who are not proven postmenopausal. Postmenopausal is defined as any of the
following:
1. Amenorrheic for 1 year or more following cessation of exogenous hormonal
treatments
2. Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the
post-menopausal range for women under 50
3. Radiation-induced oophorectomy with last menses >1 year ago
4. Chemotherapy-induced menopause with >1 year interval since last menses
5. Surgical sterilisation (bilateral oophorectomy or hysterectomy
Exclusion Criteria:
1. Prior therapy:
1. Prior systemic therapy within 2 weeks of cycle 1 day 1
2. Prior therapy with a VEGF(R) inhibitor alone or in combination with immune
checkpoint inhibitor(s).
3. Prior therapy with an anti-CTLA-4 antibody
2. Participants with active, known, or suspected autoimmune disease. Participants with
type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only
requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or
alopecia) not requiring systemic treatment are permitted to enroll.
3. Participants with a condition requiring systemic treatment with either corticosteroids
(> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within
14 days of study drug administration. Inhaled or topical steroids are permitted in the
absence of active autoimmune disease.
4. History of allergy or hypersensitivity to any monoclonal antibody
5. Previous or concurrent malignancy within 3 years of study entry, with the following
exceptions:
1. adequately treated basal or squamous cell skin cancer, superficial bladder
cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or
other noninvasive or indolent malignancy; OR
2. other solid tumors treated curatively in which the expected rate of recurrence
within 5 years is < 5%.
6. Impaired cardiovascular function or clinically significant cardiovascular diseases,
including any of the following:
1. History of acute coronary syndromes (including myocardial infarction, unstable
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) <6
months prior to screening,
2. Symptomatic congestive heart failure (i.e. Grade 2 or higher), history or current
evidence of clinically significant cardiac arrhythmia and/or conduction
abnormality <6 months prior to screening. Exceptions include
asymptomatic/well-controlled atrial fibrillation/flutter or paroxysmal
supraventricular tachycardia;
3. Uncontrolled hypertension defined as persistent elevation of systolic blood
pressure = 140 mmHg or diastolic blood pressure = 90 mmHg, despite medical
therapy
7. History of thromboembolic or cerebrovascular events = 6 months prior to the first dose
of study treatment. Examples include transient ischemic attacks, cerebrovascular
accidents, hemodynamically significant (i.e., massive or sub-massive) deep vein
thrombosis or pulmonary emboli.
Note: Individuals with either deep vein thrombosis or pulmonary emboli that does not
result in hemodynamic instability are allowed to enroll as long as they are on a
stable dose of anticoagulants for at least 4 weeks.
Note: Individuals with thromboembolic events related to indwelling catheters or other
procedures may be enrolled.
8. Known positive serology for HIV (Human immunodeficiency virus), active hepatitis B,
and/or active hepatitis C infection
9. Impaired gastrointestinal function or disease that may significantly alter the
absorption of cabozantinib (e.g., uncontrolled vomiting or malabsorption syndrome)
10. Concurrent neuromuscular disorder that is associated with the potential of elevated CK
(e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis,
spinal muscular atrophy)
11. Any other condition that would, in the Investigator's judgment, contraindicate an
individual's participation in the clinical study due to safety concerns or compliance
with clinical study procedures, e.g., infection/inflammation, intestinal obstruction,
unable to swallow medication, social/ psychological issues, etc.
12. Participants who have undergone major surgery (e.g., intracranial, intrathoracic, or
intra-abdominal surgery) = 3 weeks prior to starting study drug, minor surgery < 10
days prior to starting study drug or who have not recovered from side effects of such
procedure. Subjects must have complete wound healing from major surgery or minor
surgery before first dose of study treatment.
13. Participants that are pregnant or nursing (lactating)
14. Prisoners or individuals who are involuntarily incarcerated
15. Medical, psychiatric, cognitive or other conditions that may compromise the
participant's ability to understand the patient information, give informed consent,
comply with the study protocol or complete the study
16. Patients with leptomeningeal involvement by melanoma
17. Participants with CNS metastases or leptomeningeal carcinomatosis are not eligible
unless:
1. CNS metastases have been treated and remained stable by radiographic evaluation
at least 4 weeks after CNS directed therapy and/or:
2. There are =5 asymptomatic untreated CNS metastases measuring no larger than 10 mm
each.
3. Eligible subjects must be neurologically asymptomatic and without corticosteroid
treatment at the time of first dose of study treatment."
18. Radiation therapy for bone metastases within 2 weeks, any other radiation therapy
within 4 weeks, or systemic treatment with radionuclides within 6 weeks before first
dose of study treatment; ongoing clinically relevant complications from prior
radiation therapy are not eligible
19. 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:
20. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable
guidelines) and low-dose low molecular weight heparins (LMWH).
21. 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.
22. Administration of a live, attenuated vaccine within 30 days prior to first dose of
study treatment
23. Evidence of tumor invading the GI tract, active peptic ulcer disease, IBD,
diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute
pancreatitis, acute obstruction of pancreatic duct or common bile duct, or gastric
outlet obstruction
24. Abdominal fistula, GI perforation, bowel obstruction or intra-abdominal abscess within
6 months before first dose of study treatment. Complete healing of intra-abdominal
abscess must be confirmed before first dose of study treatment
25. Clinically significant hematuria, hematemesis, or hemoptysis of >0.5 tsp (2.5ml) of
red blood, or other history of significant bleeding within 12 weeks before first dose
of study treatment
26. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
manifestation
27. Lesions invading or encasing any major blood vessels.
28. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening
chest CT scan.
29. Serious non-healing wound/ulcer/bone fracture.
30. Moderate to severe hepatic impairment (Child-Pugh B or C).
31. Requirement for hemodialysis or peritoneal dialysis.
32. History of solid organ or allogenic stem cell transplant.
33. QTcF > 500 msec within 14 days before first dose of study treatment (Note: Could also
be listed in Inclusion as = 500 msec)
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