Subjects will receive nivolumab, ipilimumab and cabozantinib until either disease
progression, the occurrence of unacceptable drug-related toxicity or for other reason(s) for
subject withdrawal. Treatment will continue for up to 2 years unless there is disease
progression, drug intolerance or other reason for discontinuation discussed with the
principal investigator (PI). Patients with ongoing complete or partial response may
discontinue therapy after 1 year on treatment at the discretion of the treating investigator.
Inclusion Criteria:
1. All patients must have unresectable stage IIIb-IIId or IV melanoma by AJCC 8th
edition. Note: Patients with uveal melanoma are excluded from this study.
2. Age > 18 and ECOG Performance Status of 0 or 1.
3. Measurable disease by RECIST 1.1
4. Baseline tumor specimen available.
5. Recovery to baseline or ≤ Grade 1 CTCAE v4 from toxicities related to any prior
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive
therapy.
6. Adequate organ and marrow function.
7. Capable of understanding and complying with the protocol requirements and must have
signed the informed consent document.
8. Sexually active fertile subjects and their partners must agree to use medically
accepted methods of contraception (eg, 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 study treatment.
9. Female subjects of childbearing potential must not be pregnant at screening.
Exclusion Criteria:
1. Prior treatment with anti-PD-1/PD-L1 therapy, anti-CTLA-4 therapy or cabozantinib.
Prior adjuvant anti-PD-1 and/or anti-CTLA-4 therapy is allowed if relapse is greater
than 6 months from last dose.
2. Receipt of any type of small molecule kinase inhibitor (including investigational
kinase inhibitor) within 2 weeks before first dose of study treatment.
3. Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy
(including investigational) within 4 weeks before first dose of study treatment.
4. Radiation therapy for bone metastasis or brain 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.
5. Known brain metastases that are >10mm or cranial epidural disease unless adequately
treated with radiosurgery and/or surgery (including radiosurgery). Eligible subjects
must be neurologically asymptomatic and without corticosteroid requirement.
Dexamethasone < 2mg daily (or equivalent) will be allowed if discontinuation of
corticosteroids is not feasible due to post-radiation effects and patient is
asymptomatic. Patients with active, asymptomatic brain metastases that are <10mm and
no corticosteroid requirement will be allowed without radiosurgery or surgery.
6. History of active autoimmune disorder requiring immunosuppressive agents. Patients
with autoimmune disorders considered low risk, such as vitiligo and thyroiditis, will
be allowed.
7. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin
inhibitors (e.g. dabigatran), betrixaban, or platelet inhibitors (eg, clopidogrel).
Allowed anticoagulants are the following:
1. Prophylactic use of Low-dose aspirin for cardio-protection (per local applicable
guidelines) and low-dose low molecular weight heparins (LMWH) are permitted.
2. Anticoagulation with therapeutic doses of LMWH or anticoagulation with direct
factor Xa inhibitors rivaroxaban, edoxaban, or apixaban is allowed in subjects
without known brain metastases who are on a stable dose of LMWH anticoagulant for
at least 6 weeks 1week before first dose of study treatment, and who have had no
clinically significant hemorrhagic complications from the anticoagulation regimen
or the tumor.
8. The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥
1.3 x the laboratory ULN within 7 days before the first dose of study treatment.
9. The subject has uncontrolled, significant intercurrent or recent illness.
10. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks
before first dose of study treatment.
11. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
electrocardiogram (ECG) within 28 days before first dose of study treatment.
12. Pregnant or lactating females.
13. Inability to swallow tablets.
14. Previously identified allergy or hypersensitivity to components of the study treatment
formulations.
15. Diagnosis of another malignancy within 2 years before first dose of study treatment,
except for superficial skin cancers, or localized, low grade tumors deemed cured and
not treated with systemic therapy.
16. Subjects with 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.
