Sequentional Immuno Apheresis Plasma Volume Escalation Cohort Study of Reduction of Soluble Tumor Necrosis Factor Receptors 1 and 2 (sTNFR1/2) With or Without Nivolumab in Patients With Inoperable or Metastatic Solid Tumors

Inclusion Criteria:

• ● Signed informed consent
• Age ⩾ 18 years
• Able to comply with study protocol, in the investigator's judgment
• Histologically confirmed diagnosis of locally advanced unresectable, ormetastatic (Stage IV) melanoma, triple negative breast cancer, non-small celllung cancer, renal cell carcinoma
• Progressed on at least one standard of care systemic therapy (e.g., chemotherapyor immunotherapy) in advanced/metastatic disease settings prior to inclusion inthis study
• Eastern Cooperative Oncology Group Performance Status of 0 or 1
• Measurable disease according to RECIST v1.1
• Life expectancy ⩾ 3 months
• Adequate hematologic and end-organ function, defined by the following laboratorytest results, obtained within 14 days prior to initiation of study treatment:
• ANC ≥ 1.5 x 109/L
• WBC ≥ 1.5 x 109/L
• Lymphocyte count ≥ 0.5 x 109/L
• Platelet count ≥ 100 x 109/L
• Hemoglobin ≥ 10g/dL (may be achieved with transfusion support)
• Serum albumin ≥ 3.2mg/dL
• Total bilirubin ≤ x1.5 ULN
• AST and ALT ≤ x2.5 ULN (in case of liver metastasis up to x5 ULN)
• ALP ≤ 2.5 x ULN (in case of liver or bone metastasis up to x5 ULN)
• Creatinine ≤x2 ULN
• Serum uric acid ≤ x1.5 ULN
• Calcium levels within normal range
• INR≤x1.5 ULN
• Adequate psychological and physical support structure
• Female subjects may be enrolled in the trial if they are: ○ Of non-childbearing potential which is defined as: i. ⩾ 45 years of age and hasnot had menses for greater than 1 year ii. Amenorrhea for ⩾ 2 years without ahysterectomy and oophorectomy and FSH value in the postmenopausal range atscreening evaluation iii. State post hysterectomy or oophorectomy or tuballigation. 2. Of childbearing potential who have a negative pregnancy test resultwithin 14 days prior to initiation of study, and agree to remain abstinent or usea contraceptive method with a failure rate of <1% per year during the treatmentperiod (bilateral tubal ligation, male sterilization, hormone releasingintrauterine device and copper intrauterine device; any hormonal contraceptivemethod must be supplemented with a barrier method)
• Have provided tissue for biomarker analysis from a newly or recently-obtainedbiopsy (within 90 days of Study Day 1)
• Willingness to undergo tumor biopsies of accessible lesions during treatment andat progression for exploratory biomarker analysis

Exclusion Criteria:

• ● Currently participating and receiving study therapy or has participated in a studyof an investigational agent and received study therapy or used an investigation devicewithin 2 weeks of treatment initiation
• Has received prior chemotherapy, immunotherapy, radioactive or biological cancertherapy within 2 weeks prior to the treatment initiation, or who has notrecovered to CTCAE Grade 1 or better from the clinically significant AEs due tocancer therapeutics administered more than 4 weeks prior to treatment initiation,except for stable neurosensory deficits related to chemotherapy andhypothyroidism or type I diabetes due to immunotherapy
• Is expected to require any other form of systemic or localized antineoplastictherapy while in study
• Known history of hematologic malignancy or of another primary solid tumor, unlessthe subject has undergone potentially curative therapy with no evidence of thatdisease for five years. The time requirement does not apply to the tumor forwhich the subject is enrolled in the study or subjects that underwent successfuldefinitive resection of basal or squamous cell carcinoma of the skin, superficialbladder cancer, in situ cervical cancer, in situ breast cancer or other in situcancers.
• Have refused standard of care therapy CNS criteria
• Actively progressing brain metastasis meaning new or enlarging known lesions.
• Leptomeningeal metastasis
• Intracranial hemorrhage in the last six months.
• Patients with CNS metastasis will be eligible if:
• All lesions treated with radiotherapy or surgery, and are stable for at least 4 weeksprior to initiation of study treatment, and/or
• Radiographically stable metastasis without local therapy over the last 3 months priorto initiation of study treatment Cardiovascular criteria
• Unstable angina or new-onset angina within 3 months prior to initiation of study
• Symptomatic congestive heart failure defined as NYHA Class III or higher
• Myocardial infarction within 6 months prior to initiation of study
• Clinically significant hypotension, defined as systolic pressure under 90mmHg
• Concurrent therapy with ACE inhibitors
• Significant uncontrolled arrhythmias, with the exception of atrial fibrillationcontrolled for >30 days prior to initiation of study treatment
• EF<55% Coagulation criteria
• History of deep vein thrombosis or pulmonary embolism in the last 6 month.
• Active or history of hypercoagulability/thrombophilia which is not related to theunderlying condition.
• Fibrinogen serum levels >650mg/dL Active infection criteria
• Severe systemic infection within 4 weeks prior to initiation of study, including butnot limited to, hospitalization or complications of infection, bacteremia, fungemia,infected stents or indwelling devices etc.
• Signs and symptoms of infection within 2 weeks prior to initiation of study
• Positive HIV test
• Active Hepatitis B infection (chronic or acute), defined as a positive HbsAg test atscreening. Past or resolved HBV infection, defined as having a negative hepatitis Bsurface antigen and a positive total hepatitis B core antibody at screening, areeligible
• Active Hepatitis C virus infection, defined as having a positive HCV antibody test anda positive HCV RNA test at screening.
• Treatment with a live attenuated vaccine within 4 weeks prior to initiation of studyOther criteria
• Uncorrectable electrolyte abnormalities
• Known hypersensitivity to apheresis
• Current, severe, uncontrolled systemic illness other than cancer, that according tothe investigator's judgment should exclude the patient
• Any psychological, familial, sociological or geographical condition that may mappercompliance with the protocol and follow-up after treatment discontinuation
• Pregnant or breastfeeding, or intending to become pregnant during the study
• Known clinically significant liver disease, including alcoholism, cirrhosis or otherinherited liver diseases
• Inability to install central line catheter
• Treatment with anti TNF agents - infliximab (Remicade), adalimumab (Humira),certolizumab pegol (Cimzia), and golimumab (Simponi), or etanercept (Enbrel).
• Active autoimmune disease - known or suspected. Hypothyroidism or hypopituitarismadequately treated with supplemental hormones, type 1 diabetes mellitus or skindisorders (vitiligo, psoriasis, alopecia) not requiring systemic immunosuppression areeligible.
• Permanent systemic steroid therapy. Steroid treatment equal or less than 10 mgprednisolone (or equivalent) is allowed.