Platinum Chemotherapy Plus Paclitaxel With Bevacizumab and Atezolizumab in Metastatic Carcinoma of the Cervix

Inclusion Criteria:

1. Female patients must be ≥18 years of age.

2. Signed informed consent before any study-specific procedure

3. Able (in the investigator´s judgment) to comply with the study protocol

4. GOG/Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

5. Life expectancy ≥3 months

6. Histologically- or cytologically-confirmed diagnosis of metastatic (stage IVB),persistent, or recurrent cervical cancer (histologies other than squamous cell,adenocarcinoma, or adenosquamous will be excluded) not amenable for curativetreatment with surgery and/or radiation therapy. The inclusion of patients withadenocarcinoma histology will be capped to 20% of the whole study population.

7. No prior systemic anti-cancer therapy for metastatic or recurrent disease.

8. Measureable disease by RECIST v1.1 criteria.

9. A tumor specimen is mandatory at study entry.

10. Adequate organ function: Hemoglobin ≥9 g/dL ANC ≥1.5 × 109/L Lymphocyte count ≥0.5 × 109/L Platelet count ≥100 x 109/L

11. Adequate liver function: Serum albumin ≥2.5 g/dL Total serum bilirubin ≤1.5 ×ULN AST and ALT ≤2.5 × upperlimit normal (ULN) or ≤5 × ULN if tumor involvement (liver) is present

12. Adequate renal function: Patients with serum creatinine <1.5 × ULN Urine dipstick for proteinuria <2+.

13. Adequate coagulation: Blood coagulation parameters (PTT, PT/INR): PT such that international normalizedratio (INR) is ≤ 1.5 (or an in-range INR, usually between 2 and 3, if a patient ison a stable dose of therapeutic warfarin for management of venous thrombosisincluding pulmonary thromboembolus) and a PTT <1.5 × ULN.

14. Negative Test Results for Hepatitis: Negative hepatitis B surface antigen (HBsAg) test at screening Negative totalhepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb testfollowed by a negative hepatitis B virus (HBV) DNA test at screening.The HBV DNAtest will be performed only for patients who have a positive total HBcAb test. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCVantibody test followed by a negative HCV RNA test at screening.The HCV RNA test willbe performed only for patients who have a positive HCV antibody test.

15. Toxicities related to previous treatments must be recovered to < grade 2 (with theexception of alopecia).

16. Female participants must be postmenopausal (≥ 12 months of non-therapy-inducedamenorrhoea) or surgically sterile (absence of ovaries and/or uterus, or whoreceived therapeutic radiation to the pelvis) or otherwise have a negative serumpregnancy test within 7 days of the first study treatment and agree to abstain fromheterosexual intercourse or use single or combined contraceptive methods that resultin a failure rate of <1% per year during the whole treatment period of the study andfor at least 5 months (if the last study dose contained atezolizumab) or 6 months (if the last study dose contained bevacizumab) after the last dose of studytreatment.

• Abstinence is acceptable only if it is in line with the preferred and usuallifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation,symptothermal or postovulation methods) and withdrawal are not acceptablemethods of contraception

Exclusion Criteria:

1. Disease that is suitable for local therapy administered with curative intent

2. Prior radiotherapy delivered using cobalt (rather than a linear accelerator)

3. Patients with Stage IVA not amendable to concurrent chemo-radiation as primarytreatment will not be eligible.

4. Ongoing disease involving the bladder or rectum at screening/baseline

5. Evidence of abdominal free air

6. Bilateral hydronephrosis, unless it can be alleviated by ureteral stent(s) orpercutaneous drainage

7. Patients previously treated with chemotherapy except when used concurrently withradiation therapy. Patients who have received either concurrent paclitaxel withradiation therapy or carboplatin/paclitaxel as adjuvant therapy are ineligible forthe study.

8. Prior treatment with any anti-VEGF drug, including bevacizumab, CD137 agonists orimmune checkpoint blockade therapies, anti-PD1, or anti-PDL1 therapeutic antibodiesor anti-CTLA 4.

9. Patients with a concomitant malignancy other than non-melanoma skin cancer. Patientswith a prior invasive malignancy (except non-melanoma skin cancer ) who have had anyevidence of disease within the last 5 years or whose prior malignancy treatmentcontraindicates the current protocol therapy.

10. Known brain metastases or spinal cord compression. It is mandatory to perform a scanof the brain in cases of suspected brain metastases (CT or MRI) or spinal cordcompression (MRI).

11. History or evidence, following a neurological examination, of central nervous system (CNS) disorders, unless properly treated with standard medical treatment,(e.g.uncontrolled epileptic seizures). History of cerebrovascular accident (CVA, stroke),transient ischemic attack (TIA) or subarachnoid hemorrhage within six months of thefirst date of treatment on this study.

12. Patients with serious non-healing wound, ulcer, or bone fracture.

13. Acute intestinal obstruction or sub-occlusion episode in the last 6 months.

14. Active GI bleeding or GI ulcer

15. History of Crohn's disease or inflammatory bowel disease

16. Prior bowel resection ≤6 weeks preceding first study dose

17. History of diverticulitis requiring medical intervention

18. NCI CTCAE (version 5.0) grade ≥2 enteritis

19. Major surgical procedure, open biopsy or significant traumatic injury within 28 daysprior to Day 1, Cycle 1.

20. Core biopsy or other minor surgical procedure, excluding placement of a vascularaccess device, within 7 days prior to Day 1, Cycle 1.

21. Patients with active bleeding or pathologic conditions that carry high risk ofbleeding, such as known bleeding disorder, coagulopathy, or tumor involving majorvessels.

22. Current or recent (within 10 days before the first dose of study drug) chronic dailytreatment with aspirin (>325 mg/day), clopidogrel (>75 mg/day), or current or recent (within 10 days before first dose of bevacizumab) use of therapeutic oral orparenteral anticoagulants or thrombolytic agents for therapeutic purposes.

23. Patients with pre-existing Grade 2 or greater peripheral neuropathy.

24. History of any grade ≥3 venous thromboembolic event (VTE)

25. Patients with clinically significant cardiovascular disease.

26. Left ventricular ejection fraction defined by MUGA/ECHO below the institutionallower limit of normal.

27. Uncontrolled tumor-related pain

28. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures (once monthly or more frequently). Patients with indwellingcatheters (e.g., PleurX) are allowed.

29. Uncontrolled hypercalcemia (>1.5 mmol/L ionized calcium or calcium >12 mg/dL orcorrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued useof bisphosphonate therapy or denosumab.

30. History of autoimmune disease, including but not limited to myasthenia gravis,myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,inflammatory bowel disease, vascular thrombosis associated with antiphospholipidsyndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,multiple sclerosis, vasculitis, glomerulonephritis or celiac disease. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of activepneumonitis on screening chest CT scan

31. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

32. Active tuberculosis

33. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limitedto hospitalization for complications of infection, bacteremia, or severe pneumonia

34. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1

35. Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1

36. Known human immunodeficiency virus (HIV)

37. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 oranticipation that such a live attenuated vaccine will be required during the studyInfluenza vaccination should be given during influenza season only

38. Any other diseases, metabolic dysfunction, physical examination finding, or clinicallaboratory finding giving reasonable suspicion of a disease or condition thatcontraindicates the use of an investigational drug or that may affect theinterpretation of the results or render the patient at high risk from treatmentcomplications

39. Treatment with systemic immunostimulatory agents (including but not limited to IFNs,IL-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior toCycle 1, Day 1

40. Treatment with systemic immunosuppressive medications (including but not limited toprednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1The use of corticosteroids is allowed as premedication for paclitaxel-based regimen.All patients should be premedicated prior to receiving chemotherapy (including withcorticosteroids) according to the prescription information of paclitaxel andcisplatin/carboplatin and the institutional standard of care guidance.

41. Currently participating or has participated in a study of an investigational agentand received study therapy or used an investigational device within 4 weeks prior tothe first dose of study treatment.

42. Prior anti-cancer monoclonal antibody (mAb), prior chemotherapy, targeted smallmolecule therapy as first line treatment for the treatment of metastatic orrecurrent cervical cancer.

43. Women that are breastfeeding or pregnant

44. Known hypersensitivity to bevacizumab, atezolizumab or any of theirs excipients (including Cremophor)

45. Demonstration of any other neurological or metabolic dysfunction, found uponphysical examination or laboratory tests involving a reasonable suspicion of theexistence of a disease or condition that contraindicates the use of an experimentaldrug, or that involves an increased risk to the patient of treatment-relatedcomplications

46. No medical or psychiatric illness that may impede the performance of a systemic orsurgical treatment.