Study of Cemiplimab Plus Ziv-Aflibercept for Subjects With Metastatic Uveal Melanoma

Inclusion Criteria:

• Provision of signed and dated informed consent form.

• Male or female, aged >/= 18 years old.

• Life expectancy of greater than 3 months in the opinion of the investigator.

• Must be willing and able to provide informed consent signed by study patient orlegally acceptable representative, as specified by health authorities andinstitutional guidelines.

• Patients must have metastatic uveal melanoma, either initial presentation orrecurrent, that is histologically diagnosed.

• Patients with histologically or cytologically confirmed metastatic melanoma orcutaneous, mucosal or unknown primary origin are also eligible. This includes AJCCstage IV or advanced/inoperable stage III. This also includes patients with ahistory of lower stage melanoma and subsequent recurrent metastatic disease that iseither locally/regionally advanced/inoperable disease or distant metastases. Thesepatients must have previously received anti-PD1 immunotherapy (nivolumab orpembrolizumab) as monotherapy or in combination and later experienced diseaseprogression. Patients with BRAF V600 mutant melanoma must have previously receivedBRAF targeted therapy for metastatic melanoma and later experienced diseaseprogression. Patients who refuse or decline to receive BRAF targeted therapy orprefer to delay or were intolerant of BRAF targeted therapy are eligible

• Patients must have ECOG performance status of 0-1.

• Patients must have measurable disease, according to RECIST version 1.1.

• Patients must have normal organ and marrow function as defined in protocol.

• Urine protein should be screened by urinalysis for Urine Protein Creatinine Ratio (UPCR). For UPCR > 1, a 24-hour urine protein should be obtained, and the levelshould be <500 mg.

• An echocardiogram should be performed at baseline in all patients. Ejection fraction (EF) from baseline echocardiogram must be within the institutional limits of normalas determined by the reading cardiologist.

• Patients on full-dose anticoagulants (e.g., warfarin) with PT INR >1.5 are eligibleprovided that both of the following criteria are met:

1. The patient has an in-range INR (usually between 2 and 3) on a stable dose oforal anticoagulant or on a stable dose of low molecular weight heparin.

2. The patient has no active bleeding or pathological condition that carries ahigh risk of bleeding (e.g., tumor involving major vessels or known varices).

• A patient may be treatment naïve. However, prior systemic treatments for metastaticuveal melanoma are allowed. There is no limit on the number of prior regimens formetastatic uveal melanoma. However, no prior therapy with bevacizumab, afliberceptor cemiplimab.

• Patients must be free of active brain metastasis by contrast-enhanced CT/MRI scanswithin 4 weeks prior to enrollment. If known to have prior brain metastases, thesemust have been adequately managed with standard of care radiation therapy,stereotactic radiosurgery or surgery prior to registration on the study.

• For Women of childbearing potential: use of highly effective contraception for atleast 2 or more menstrual cycles prior to screening and agreement to use such amethod during study participation and for at least 180 days after the end of studydrugs administration.

• For males of reproductive potential: use of condoms or other methods to ensureeffective contraception with partner For at least 1 month prior to screening andagreement to use such a method during study participation and for at least 180 daysafter the end of study drugs administration.

Exclusion Criteria:

• Pregnancy or lactation.

• Treatment with another investigational drug or other systemic intervention for uvealmelanoma within 4 weeks of initiation of study drugs. Patients must not haveradiotherapy within the preceding 4 weeks.

Patients must have recovered from adverse events due to agents administered more than 4 weeks earlier.

• Patients must be at least 4 weeks from major surgery and have fully recovered fromany effects of surgery and be free of significant detectable infection.

• Patients must not have autoimmune disorders or conditions of immunosuppression thatrequire current ongoing treatment with systemic corticosteroids (or other systemicimmunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) orcontinuous use of topical steroid creams or ointments or ophthalmologic steroids. Ahistory of occasional (but not continuous) use of steroid inhalers is allowed.

Replacement doses of steroids for patients with adrenal insufficiency are allowed. Patients who discontinue use of these classes of medication for at least 2 weeks prior to enrollment are eligible if, in the judgment of the treating physician investigator, the patient is not likely to require resumption of treatment with these classes of drugs during the study.

• Exclusion from this study also includes patients with a history of symptomaticautoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, Sjögren's syndrome, autoimmunevasculitis [e.g., Wegener's granulomatosis]); motor neuropathy considered ofautoimmune origin (e.g., Guillain-Barre Syndrome and Myasthenia Gravis); othercentral nervous system autoimmune disease (e.g., poliomyelitis, Multiple sclerosis).

• Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent)within 4 weeks prior to the first dose of cemiplimab/placebo. NOTE: Patients whorequire brief course of steroids (eg, prophylaxis for imaging assessments due tohypersensitivity to contrast agents) are not excluded. People taking steroids forphysiologic replacement (ie, adrenal insufficiency) are NOT excluded.

• Prior allogeneic stem cell transplantation, or autologous stem cell transplantation.

• Patients who have permanently discontinued anti-cancer immune modulating therapiesdue to drug related toxicity.

• Encephalitis, meningitis, or uncontrolled seizures in the year prior toscreening/enrollment.

• History of immune related pneumonitis within the last 5 years.

• History of interstitial lung disease (eg, idiopathic pulmonary fibrosis, organizingpneumonia) or active, noninfectious pneumonitis that required immune-suppressivedoses of glucocorticoids to assist with management. A history of radiationpneumonitis in the radiation field is permitted as long as pneumonitis resolved ≥6months prior to the enrollment date.

• Patients with a history of solid organ transplant (patients with prior cornealtransplant(s) are not excluded).

• Patients with autoimmune hypothyroid disease or type I diabetes on replacementtreatment are eligible.

• Patients must not have a history of inflammatory bowel disease or diverticulitis (history of diverticulosis is allowed).

• Patients must not have other significant medical, surgical, or psychiatricconditions or require any medication or treatment that in the opinion of theinvestigator may interfere with compliance, make the administration of cemiplimabhazardous or obscure the interpretation of AEs, such as a condition associated withfrequent diarrhea.

• Patients must not have an active infection requiring current treatment withparenteral antibiotics.

• Cardiac: No evidence of congestive heart failure, symptoms of coronary arterydisease, myocardial infarction less than 6 months prior to entry, serious cardiacarrhythmias, or unstable angina.

• Central nervous system: No history of cerebrovascular accident or transient ischemicattacks within the past 6 months.

• Serious or non-healing wound, ulcer, or bone fracture.

• History of abdominal fistula, gastrointestinal perforation, or intra-abdominalabscess within 4 weeks of initiating study treatment.

• Patients with the following invasive procedures:

• Major surgical procedure, open biopsy or significant traumatic injury within 4weeks of Day 1 of study therapy.

• Anticipation of need for major surgical procedures during the course of thestudy.

• Minor surgical procedures, fine needle aspirations or core biopsies within 7days prior to Day 1 of study therapy. Central venous catheter placements arepermitted to be completed 7 or more days prior to Day 1 of study therapy.However, peripherally inserted central catheter (PICC or PIC line) may beplaced at any time prior to or during study therapy.

• Patients with clinically significant cardiovascular or cerebrovascular disease:

• History of cerebrovascular accident or transient ischemic attack within past 6months

• Uncontrolled hypertension, defined as blood pressure >150/100 mm Hg or systolicBP >180 mm Hg if diastolic blood pressure <90 mm Hg, on at least 2 repeateddeterminations on separate days within past 3 months.

• Myocardial infarction, coronary artery bypass grafting (CABG) or unstableangina within the past 6 Months.

• New York Heart Association grade III or greater congestive heart failure,serious cardiac arrhythmia requiring medication, unstable angina pectoriswithin past 6 months.

• Clinically significant peripheral vascular disease within past 6 months.

• Pulmonary embolism, deep vein thrombosis (DVT), or other thromboembolic eventwithin past 6 months.

• History of tumor-related or other serious hemorrhage, bleeding diathesis, orunderlying coagulopathy.

• PT INR >1.5 unless the patient is on full-dose warfarin.

• Patients who have other current malignancies are not eligible. Patients with othermalignancies are eligible if they have been continuously disease free for > 3 yearsprior to the time of enrollment. Patients with prior history at any time of any insitu cancer, lobular carcinoma of the breast in situ, cervical cancer in situ,atypical melanocytic hyperplasia or melanoma in situ are eligible. Patients withprior history of basal or squamous skin cancer are eligible. Patients who have hadmultiple primary melanomas are eligible.

• Receipt of a live vaccine within 28 days of the enrollment date.

• Women of childbearing potential or sexually active men, who are unwilling topractice highly effective contraception for at least 2 or more menstrual cycles (women) or 1 month (men) prior to screening, during the study, and for at least 180days after the last dose of study drug(s).