F16IL2 Plus Paclitaxel in Metastatic Merkel Cell Carcinoma

Inclusion Criteria:

• Patients with advanced or metastatic Merkel cell carcinoma (MCC) not amenable tosurgery and who have not received previous systemic therapy with taxanes; diagnosis ofMCC must be histologically confirmed (evaluation of primary lesions or advanceddisease) and endorsed by the IMMOMEC central dermatopathology center (central reviewof diagnosis at the Department of General Dermatology, Medical University of Graz).Patients must be amenable for paclitaxel treatment according to the discretion of theprincipal investigator

• Patients aged ≥ 18 ≤ 75 years

• ECOG performance status ≤ 1

• Patients must have measurable disease including cutaneous and subcutaneous metastasesas defined by RECIST v.1.1 criteria or immune related response Criteria (irRC) asassessed by CT or MRI and/or ultrasound within 4 weeks before the first study drugadministration.

• All acute side effects from any prior therapy must have resolved to National CancerInstitute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ≤ 1;.

• Adequate hematologic, liver and renal function:

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L,haemoglobin (Hb) ≥ 9.0 g/dl

• Alkaline phosphatase (AP), alanine aminotransferase (ALT) and/or aspartateaminotransferase ≤ 3 x upper limit of reference range (ULN), and total bilirubin ≤ 2.0 mg/gL unless liver involvement by the tumor, in which case the transaminaselevels could be ≤ 5 x ULN

• Creatinine ≤ 1.5 UL or 24 h creatinine clearance ≥ 50 mL/min

• Negative serum pregnancy test for females of childbearing potential within 14 days ofstarting treatment

• If of childbearing potential, agreement to use adequate contraceptive methods (e.g.,oral contraceptives, condoms, or other adequate barrier controls, intrauterinecontraceptive devices, or sterilization) beginning at the screening visit andcontinuing until 3 months following last treatment with study drug

• Evidence of a personally signed and dated EC-approved Informed Consent form indicatingthat the patient (or legally acceptable representative) has been informed of allpertinent aspects of the study

• Willingness and ability to comply with the scheduled visits, treatment plan,laboratory tests and other study procedures

Exclusion Criteria:

• Life expectancy of less than 3 months

• Any previous taxanes therapy

• Previous or concurrent CLL patients

• Any other malignancy from which the patient has been disease-free for less than 2years prior to study entry, with the exception of adequately treated and curedcervical carcinoma in situ, basal or squamous cell carcinoma, superficial bladdercancer, or in situ melanoma

• Presence of uncontrolled infections or other severe concurrent disease, which, in theopinion of the investigator, would place the patient at undue risk or interfere withthe study

• Presence of known brain metastases

• Chronic-active hepatitis B, C, or HIV

• Severe cardiovascular disease:

• History of acute or subacute coronary syndromes including myocardial infarction,unstable or severe stable angina pectoris

• Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria)

• Irreversible cardiac arrhythmias requiring permanent medication

• LVEF < 50% and/or abnormalities observed during baseline 2D-ECHO or 12-lead ECGinvestigations

• Uncontrolled hypertension

• Ischemic peripheral vascular disease (Grade IIb-IV)

• Severe rheumatoid arthritis; or other uncontrolled autoimmune disease

• Severe diabetic retinopathy

• History of allograft or stem cell transplantation

• Major trauma including major surgery (e.g. visceral surgery) within 4 weeks ofadministration of study treatment

• Known history of allergy to IL-2, taxanes, cremophor or other intravenouslyadministered human proteins/peptides/antibodies

• Pregnancy or breast-feeding. Female patient must agree to use effective contraception,or be surgically sterile or postmenopausal. The definition of effective contraceptionwill be based on the European guideline ICH M3 rev 2.

• Treatment with an investigational study drug within four weeks before beginning oftreatment with F16IL2

• Previous treatment with monoclonal antibodies for biological therapy in the four weeksbefore administration of study treatment

• Any conditions that in the opinion of the investigator could hamper compliance withthe study protocol.