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

● Signed informed consent

* Age ⩾ 18 years

* Able to comply with study protocol, in the investigator's judgment

* Histologically confirmed diagnosis of locally advanced unresectable, or metastatic (Stage IV) melanoma, triple negative breast cancer, non-small cell lung cancer, renal cell carcinoma

* Progressed on at least one standard of care systemic therapy (e.g., chemotherapy or immunotherapy) in advanced/metastatic disease settings prior to inclusion in this 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 laboratory test 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 has not had menses for greater than 1 year ii. Amenorrhea for ⩾ 2 years without a hysterectomy and oophorectomy and FSH value in the postmenopausal range at screening evaluation iii. State post hysterectomy or oophorectomy or tubal ligation. 2. Of childbearing potential who have a negative pregnancy test result within 14 days prior to initiation of study, and agree to remain abstinent or use a contraceptive method with a failure rate of \<1% per year during the treatment period (bilateral tubal ligation, male sterilization, hormone releasing intrauterine device and copper intrauterine device; any hormonal contraceptive method must be supplemented with a barrier method)

* Have provided tissue for biomarker analysis from a newly or recently-obtained biopsy (within 90 days of Study Day 1)

* Willingness to undergo tumor biopsies of accessible lesions during treatment and at progression for exploratory biomarker analysis

All lesions treated with radiotherapy or surgery, and are stable for at least 4 weeks prior to initiation of study treatment, and/or

Radiographically stable metastasis without local therapy over the last 3 months prior to 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 fibrillation controlled 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 the underlying condition.

* Fibrinogen serum levels \>650mg/dL

Active infection criteria

Severe systemic infection within 4 weeks prior to initiation of study, including but not 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 at screening. Past or resolved HBV infection, defined as having a negative hepatitis B surface antigen and a positive total hepatitis B core antibody at screening, are eligible

Active Hepatitis C virus infection, defined as having a positive HCV antibody test and a positive HCV RNA test at screening.

Treatment with a live attenuated vaccine within 4 weeks prior to initiation of study Other criteria

Uncorrectable electrolyte abnormalities

Known hypersensitivity to apheresis

Current, severe, uncontrolled systemic illness other than cancer, that according to the investigator's judgment should exclude the patient

Any psychological, familial, sociological or geographical condition that may mapper compliance 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 other inherited 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 hypopituitarism adequately treated with supplemental hormones, type 1 diabetes mellitus or skin disorders (vitiligo, psoriasis, alopecia) not requiring systemic immunosuppression are eligible.

Permanent systemic steroid therapy. Steroid treatment equal or less than 10 mg prednisolone (or equivalent) is allowed.

What this study is about