Efficacy and Safety of BCD-100 (Anti-PD-1) in Combination With Platinum-Based Chemotherapy and Bevacizumab in Patients With Recurrent, Persistent or Metastatic Cervical Cancer (CAESURA)

Inclusion Criteria:

1. Signed Informed Consent Form and the subject's ability to follow the Protocolrequirements;

2. Age: 18 years and older at the signing of the informed consent;

3. Histologically verified (documented) adenomatous, adenosquamous, or squamous cervicalcancer;

4. Newly diagnosed metastatic cervical cancer or recurrent/persistent cervical cancer;

5. Availability of archival histological tumor material (paraffin blocks) or consent tobiopsy;

6. ECOG performance status of 0 or 1;

7. At least one RESICT 1.1-defined measurable target lesion confirmed by an independentreview;

8. Patients with reproductive potential must agree to practice acceptable methods ofbirth control throughout the entire trial period, starting from signing the informedconsent and up to 24 weeks after the last dose of investigational product.

Exclusion Criteria:

1. Indications for radical therapy (surgical or radiotherapy);

2. Prior systemic treatment for recurrent, secondarily progressive or initiallymetastatic disease;

3. Chemotherapy, and / or radiation therapy, and / or chemo-radiation therapy for earlystages of cervical cancer with disease progression / recurrence earlier than 6 monthsafter the end of therapy;

4. Patients with severe concomitant factors or the effects of their treatment (hemorrhage, perforation, fistula);

5. Central nervous system (CNS) metastases;

6. Concomitant diseases or conditions which pose a risk of AE development during studytreatment:

7. uncontrolled hypertension, defined as systolic > 150 mm Hg or diastolic > 90 mmHg;

8. stable angina functional class III-IV;

9. unstable angina or myocardial infarction less than 6 months prior torandomization;

10. NYHA Grade III-IV congestive heart failure;

11. atopic asthma, Stage III-IV COPD, angioedema;

12. severe respiratory failure;

13. any other diseases which pose unacceptable risk of AE development during studytreatment in Investigator's opinion;

14. Active or known or suspected autoimmune disease (subjects with Type 1 diabetesmellitus, hypothyroidism only requiring hormone replacement, or skin disorders (vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted toenroll);

15. Condition requiring systemic treatment with either corticosteroids or otherimmunosuppressive medications within 14 days prior to randomization;

16. Established diagnosis of coagulopathy and / or clinically significant bleeding,including nasal bleeding;

17. The need for regular intake of anticoagulants, antiplatelet agents, platelet functioninhibitors, or their course application less than 1 month before being included in thestudy;

18. Hematologic disorders: neutrophils <1500/mcl or platelets <100 000/mcl or hemoglobin <90 g/l;

19. Renal disorders: creatinine ≥ 1.5 x UNL;

20. Hepatic disorders: bilirubin ≥ 1.5 x UNL (excluding Gilbert's syndrome if bilirubin < 50 µmol/l) or AST/ALT ≥ 3 x UNL (excluding subjects with liver metastases if AST/ALT < 5 x UNL) or alkaline phosphatase ≥ 5 x UNL;

21. Any anti-cancer therapy less than 28 days prior to randomization;

22. Previous use of PD-1/PD-L1/PD-L2/CTLA-4 agent;

23. Previous use of VEGF/VEGFR inhibitors, including bevacizumab, ramucirumab, afliberceptand tyrosine kinase inhibitors;

24. Concomitant cancer (except for cervical carcinoma in situ after radical surgery orbasal cell/ squamous cell carcinoma after radical surgery);

25. Clinically significant (≥2 degree) peripheral neuropathy or hearing impairment;

26. Any condition that prevents a patient from following the Protocol procedures (dementia, neurological or mental disorders, drug/alcohol abuse, etc.);

27. Simultaneous participation in other clinical trials , participation in other clinicaltrials within 30 days prior to the first dose of the investigational product;

28. Acute infection or the acute phase of chronic infection within 28 days prior the firstdose of the investigational product;

29. Active HBV/HCV/HIV infection, active syphilis;

30. Patients unable to receive an IV infusions;

31. Patients unable to receive an IV contrast agent;

32. Hypersensitivity to any of the components of BCD-100, bevacizumab, paclitaxel,cisplatin (or carboplatin);

33. Life expectancy less than 6 months;

34. Significant adverse events (AE) of previous therapy excluding chronic and/orirreversible events which cannot affect study drug safety evaluation (e.g. alopecia);

35. Pregnancy or breast-feeding.