Platinbasierte Chemotherapie mit Atezolizumab und Niraparib bei Patientinnen mit rezidivierendem Ovarialkarzinom (ANITA)

1. Patients ≥ 18 years old

2. Life expectancy ≥3 months

3. Signed informed consent and ability to comply with treatment and follow-up

4. Histologically confirmed diagnosis (cytology alone excluded) of high- grade serous or endometrioid ovarian, primary peritoneal or tubal carcinoma.

5. BReast CAncer (BRCA) mutational status is known (germline or somatic)

6. Relapsed disease more than 6 months after the last platinum dose

7. No more than 2 prior lines of chemotherapy are allowed, and the last one must contain a platinum-based regimen

8. At least one measurable lesion to assess response by RECIST v1.1 criteria.

9. Archival tumor sample must be available. In the absence of an archival biopsy, a tumour tissue biopsy will need to be collected prior to study enrolment.

10. Performance status determined by Eastern Cooperative Oncology Group (ECOG) score of 0-1

11. Normal organ and bone marrow function:

• Haemoglobin ≥10.0 g/dL
• Absolute neutrophil count (ANC) ≥1.5 x 109/L
• Lymphocyte count ≥0.5 × 109/L
• Platelet count ≥100 x 109/L
• Total bilirubin ≤1.5 x institutional upper limit of normal (ULN)
• Serum albumin ≥2.5 g/dL
• Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤2.5 x ULN, unless liver metastases are present in which case they must be ≤5 x ULN
• Serum creatinine ≤1.5 x institutional ULN or calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation
• Patients not receiving anticoagulant medication must have an International Normalized Ratio (INR) ≤1.5 and an Activated ProThrombin Time (aPTT) ≤1.5 x ULN.

12. Negative Test Results for Hepatitis.

13. Toxicities related to previous treatments must be recovered to < grade 2

14. Female participants must be postmenopausal or surgically sterile or otherwise have a negative serum pregnancy test within 7 days of the first study treatment and agree to abstain from heterosexual intercourse or use single or combined contraceptive methods.

15. Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment.

16. Participant must agree to not breastfeed during the study or for 180 days after the last dose of study treatment.

1. Non-epithelial tumor of the ovary, the fallopian tube or the peritoneum.

2. Ovarian tumors of low malignant potential or low grade

3. Other malignancy within the last 5 years except curatively treated non-melanoma skin cancer, in situ cancer of the cervix and ductal carcinoma in situ (DCIS)

4. Major surgery within 4 weeks of starting study treatment or patients who have not completely recovered (Grade ≥ 2) from the effects of any major surgery at randomization

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

6. Administration of other chemotherapy drugs, anticancer therapy or anti-neoplastic hormonal therapy, or treatment with other investigational agents or devices within 28 days prior to randomization, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, or anticipation to do it during the trial treatment period (non-investigational hormonal replacement therapy is permitted)

7. Palliative radiotherapy (e.g., for pain or bleeding) within 6 weeks prior to randomization or patients who have not completely recovered (Grade ≥ 2) from the effects of previous radiotherapy

8. Current or recent (within 10 days prior to randomization) chronic use of aspirin (>325 mg/day) or clopidogrel (>75 mg/day)

9. Clinically significant (e.g. active) cardiovascular disease

10. Resting ECG with corrected QT interval (QTc) >470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome

11. Left ventricular ejection fraction defined by multigated acquisition/echocardiogram (MUGA/ECHO) below the institutional lower limit of normal (only applicable for patients intended to be treated with pegylated liposomal doxorubicin)

12. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory (within 4 weeks prior to randomization) in case of suspected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to randomization) in case of suspected spinal cord compression

13. History or evidence upon neurological examination of central nervous system (CNS) disorders (e.g. uncontrolled epileptic seizures) unless adequately treated with standard medical therapy

14. Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease

15. Uncontrolled tumor-related pain

16. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., PleurX) are allowed

17. Uncontrolled hypercalcemia (>1.5 mmol/L ionized calcium or calcium >12 mg/dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab

18. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment related complications

19. Pregnant or lactating women

20. Simultaneously receiving therapy in any interventional clinical trial

21. Prior treatment with CD137 agonists or immune checkpoint stimulating or blockade therapies, such as anti−PD1, anti−PDL1 or anti-CTLA4 therapeutic antibodies

22. Treatment with systemic immunostimulatory agents (including but not limited to interferon-alpha (IFN-α) and interleukin-2 (IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to Cycle 1, Day 1

23. Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor (TNF) agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial

24. 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 anti-phospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis

25. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis

26. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV)

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

28. Active tuberculosis

29. Administration of a live, attenuated vaccine (including against influenza) within 4 weeks prior to Cycle 1, Day 1 or anticipation that it will be administered at any time during the treatment period of the study

30. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

31. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or to any component of the atezolizumab formulation or allergy to any of the other drugs included in the protocol or their solvents (including to Cremophor®)

32. Patient has received prior treatment with a poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitor in the recurrent setting or has participated in a study where any treatment arm included administration of a PARP inhibitor in the recurrent setting, unless the patient is unblinded and there is evidence of not having received a PARP inhibitor

33. Patient has had any known ≥Grade 3 hematological toxicity anemia, neutropenia or thrombocytopenia due to prior cancer chemotherapy that persisted >4 weeks and was related to the most recent treatment

34. Patient has any known history or current diagnosis of Myelodysplasic syndrome (MDS) or Anaplastic Myeloid Leukemia (AML)

35. Previous allogeneic bone marrow transplant or previous solid organ transplantation

36. Patient has a condition (such as transfusion dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that might confound the study results or interfere with the patient's participation for the full duration of the study treatment

37. Participant has any known hypersensitivity to niraparib components or excipients