Safety and Preliminary Efficacy of MBS8(1V270) in Cancer Patients With Advanced Solid Tumours

Inclusion Criteria:

1. Male or female aged ≥ 18 years
2. Diagnosis of histologically- or cytologically-confirmed solid tumour that is advancedand with progression. No standard treatment exists, or the subject refuses standardtreatment. Experimental immunotherapy appears as feasible exploratory treatment optionas per investigator assessment.
3. Tumour lesion(s) accessible to serial biopsies.
4. Must be willing and able to comply with scheduled visits, treatment schedule,laboratory tests, tumour biopsies.
5. Measurable disease according to RECIST V1.1. Previously irradiated lesions aremeasurable if subsequent progression is documented.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
7. Life expectancy > 3 months as assessed by the investigator.
8. Adequate bone marrow, cardiopulmonary, renal and hepatic functions:

• Haemoglobin ≥5.6 mmol/L (≥ 90 g/dL) (without transfusion or erythropoietintherapy within 4 weeks prior to therapy);
• Neutrophils ≥1.5 x 109/L, without growth factor stimulation within 3 weeks priorto the blood test;
• Platelet count ≥ 75 × 109/L;
• Serum creatinine ≤ 1.25 times ULN or creatinine clearance ≥50 mL mL/min (byCKD-EPI formula);
• Hepatic function: AST and ALT ≤ 2.5 x ULN; (5 × ULN in the case of livermetastases); bilirubin ≤ 1.5 × ULN except in case of Gilbert's disease and 2 ×ULN in case of liver metastases.

9. All subjects of childbearing potential (defined as < 2 years after last menstruationor not surgically sterile) must have a negative highly sensitive pregnancy test atscreening (urine/serum) and agree to use highly effective method for contraceptionaccording to the European Union (EU) Clinical Trial Facilitation Group guidance fromtime of signing the informed consent form (ICF) until at least 120 days after the lastadministration of trial drug. The partners of subjects with childbearing potentialmust also apply contraceptive methods and are recommended not to donate sperm.
10. Ability to understand and sign the ICF.

Exclusion Criteria:

1. Has had biologic, hormonal, anti-neoplastic chemotherapy, or radiation therapy within 4 weeks prior to screening (6 weeks required for nitrosourea or mitomycin) except formedications with half-lives <5.5 days.
2. Metastatic disease that involves major airways or blood vessels, or centrally locatedmediastinal tumour masses of large volume with close relation to the mayor airwayswhere tumour necrosis may cause perforation or severe bleeding episodes. Primary ormetastatic intestinal disease in situ where tumour necrosis may cause gastrointestinalperforation.
3. Use of investigational agent in the 4 weeks or 5 half-lives prior to first dose ofMBS8(1V270), whichever is shortest.
4. Major surgical procedure within 14 days prior to the first trial drug dose.
5. Has a history of another primary malignancy, except for:

• Malignancy treated with curative intent and with no known active disease within 2years prior to first dose of MBS8(1V270).
• Adequately treated non-invasive basal skin cancer or squamous cell skincarcinoma.
• Adequately treated uterine cervical cancer stage 1B or less.

6. Treatment with systemic immunosuppressive medication (including but not limited tocorticosteroids (>10 mg prednisone per day or equivalent, except topical or inhaled),cyclophosphamide, azathioprine, methotrexate, thalidomide, anti-IL-6 receptor agentsand anti-TNFα agents) within 2 weeks prior to initiation of trial treatment, oranticipation of need for systemic immunosuppressive medication during trial treatment.
7. Treatment with androgen deprivation therapies such as luteinizing-hormone releasinghormone (LHRH) (gonadotropin-hormone releasing hormone [GnRH]) agonists within 2 weeksprior to initiation of trial treatment.
8. Ongoing immune-related adverse events (irAEs) and/or AEs ≥ Grade 2 not resolved fromprevious therapies except vitiligo, resolved atopy, limited psoriasis, stableneuropathy Grade 2, hair loss, and stable endocrinopathies with substitutive hormonetherapy.
9. Has uncontrolled intercurrent or chronic illness, but not limited to, ongoing oractive infection such as hepatitis B or C, human immunodeficiency virus (HIV), immunedysfunction such as autoimmune disease, psychiatric illness such as depression orsuicidal tendency or social situations that would limit compliance with trialrequirements.
10. Has active or history of immunologic-mediated disease, including but not limited tomyasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus,rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, antiphospholipidantibody syndrome, Wegener granulomatosis, Sjogren's syndrome or Guillain-Barrésyndrome.
11. Has clinically significant cardiac disease, including:

• Known congestive heart failure Grade III or IV by the New York Heart FailureAssociation (see Appendix A);
• Myocardial infarction within 6 months prior to signing the ICF;
• Onset of unstable angina within 6 months prior to signing the ICF.

12. History of severe allergic episodes.
13. Known hypersensitivity to any component of MBS8(1V270).
14. Has a history of seizure disorders uncontrolled on medication.
15. Has a history of clinically significant coagulation or bleeding disorders orabnormalities.
16. Abnormal or clinically significant coagulation parameters at the discretion of theinvestigator, i.e.:

• International Normalized Ratio (INR);
• Activated Partial Thromboplastin Time (APTT). Subjects being treated withanticoagulants are excluded if the coagulation parameters are outside thetherapeutic intervals as described in the Summary of Product Characteristics (SmPC) for the administered treatment.

17. Women of childbearing potential who deny remaining abstinent (refrain fromheterosexual intercourse) or do not use a highly effective form of contraception thatresults in a failure rate of < 1% per year during the treatment period and up 120 daysafter the last trial drug administration.
18. Men of reproductive potential who deny to follow accepted contraception methods duringtreatment and up to 120 days after the last trial drug administration.
19. Pregnant or lactating women.
20. Has a history or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results of the trial, interfere with the subject'sparticipation for the full duration of the trial, make administration of the trialdrugs hazardous, or make it difficult to monitor adverse effects such that it is notin the best interest of the subject to participate, in the opinion of the treatinginvestigator.
21. Has an autoimmune disorder requiring immune modulating treatment (>10 mg prednisoneper day or equivalent, except topical or inhaled) during the last 2 years prior tofirst dose of MBS8(1V270).