Platinum-based Chemotherapy With Atezolizumab and Niraparib in Patients With Recurrent Ovarian Cancer
Platinum-based Chemotherapy With Atezolizumab and Niraparib in Patients With Recurrent Ovarian Cancer
Atezolizumab in this study is expected to have a positive benefit-risk profile for the
 treatment of patients with platinum-sensitive relapse of ovarian cancer. Of interest,
 atezolizumab is being investigated also in combination with platinum-based doublet
 chemotherapy in second line (2L)/ third line (3L) platinum-sensitive recurrent ovarian cancer
 patients in ATALANTE (NCT02891824), which also includes bevacizumab in the combination. The
 study is proceeding as expected after >100 patients enrolled and under independent Data
 Monitoring Committee (IDMC) supervision.

 Platinum-containing therapy is considered the treatment of choice for patients with
 platinum-sensitive relapse. However the duration of response and the prolongation of the
 progression free interval with chemotherapy are usually brief, among other because these
 chemotherapy regimens cannot be continued until progression as they are associated with
 neurological, renal and hematological toxicity and cannot generally be tolerated for more
 than about 6 to 9 cycles.

 Niraparib received FDA approval in March 2017 as maintenance treatment of adult patients with
 recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete
 or partial response to platinum-based chemotherapy. Recently, the European Medicines Agency
 (EMA) has also approved niraparib as maintenance monotherapy. Despite the progress brought
 about by niraparib, there is a need for a more effective treatment to extend the progression
 free interval in this patient population. The combination with immune checkpoint inhibitors
 such as anti-death protein 1 (anti-PD1) or anti-death protein ligand 1 (anti-PD-L1) has a
 compelling rationale to this aim, especially under the light of the emerging clinical data of
 this combination.

 The use of atezolizumab concurrent to platinum-containing chemotherapy followed by niraparib
 as maintenance therapy after completion of chemotherapy, as per normal clinical practice, may
 provide further benefit to patients in terms of prolonging the progression free interval and
 increasing the interval between lines of chemotherapy, hence delaying further hospitalization
 and the cumulative toxicities associated with chemotherapy. Additionally, preliminary studies
 with atezolizumab suggest an acceptable tolerability profile for long term clinical use in
 recurrent ovarian cancer patients and other indications.
Inclusion Criteria:

 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. Mandatory de novo tumor biopsy (collected within 3 months prior to randomization) sent
 to HistoGene X as a formalin-fixed, paraffin-embedded (FFPE) sample for PD-L1 status
 determination for randomization.

 10. Two additional tumour samples are needed: Archival tumor sample must be available for
 exploratory PD-L1 testing in archival tissue and archival or "de novo" tissue sample
 for biomarkers must also be available.

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

 12. 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.

 13. Negative Test Results for Hepatitis.

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

 15. 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.

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

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

 Exclusion Criteria:

 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

 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 or within 5 months after the final dose of
 atezolizumab.

 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. Patients that received PARP inhibitor as front line are eligible for
 the study. The duration of exposure to PARPi following front line therapy needs to be
 ≥18 months for BRCA mutated patients and ≥ 12 months for BRCA wild type patients.

 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