| Eligibility |
Inclusion Criteria:
1. Female Patients must be =18 years of age.
2. Signed informed consent and ability to comply with treatment and follow-up.
3. Patients with histologically confirmed progressive non-mucinous epithelial ovarian
cancer, primary peritoneal adenocarcinoma and / or fallopian-tube adenocarcinoma
4. Patients with PD-L1 status determined for stratification on mandatory de novo biopsy
sent to central laboratory as a formalin-fixed, paraffin-embedded (FFPE) sample.
- Cell pellet from pleural effusion, or ascites or lavage are not acceptable.
- For core needle biopsy specimens, at least three cores should be obtained.
Biopsies must be obtained in a manner that minimizes risks. If the location of
the tumor renders tumor biopsy medically unsafe or not feasible, patient
eligibility should be discussed with the sponsor.
5. Patients whose disease has relapsed more than 6 months from the last dose of platinum
before randomization:
1. criterion for relapse can be according to RECIST v1.1, CA-125 (GCIG) or clinical
symptoms
2. the interval between last dose of platinum and entry in the study should be free
of new anti-cancer treatment, with the exception of a maintenance therapy which
is allowed up to 21 days before study entry.
6. Patients with one or 2 prior lines of chemotherapy. The last line of chemotherapy
should have included platinum.
7. Availability at the study site of representative FFPE tumor sample from surgery during
front line therapy, at best before chemotherapy
8. Patients must have normal organ and bone marrow function :
1. Haemoglobin = 10.0 g/dL.
2. Absolute neutrophil count (ANC) = 1.5 x 109/L.
3. Platelet count = 100 x 109/L.
4. Total bilirubin = 1.5 x institutional upper limit of normal (ULN).
5. Aspartate aminotransferase /Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT))
and Alanine aminotransferase /Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) =
2.5 x ULN, unless liver metastases are present in which case they must be = 5 x
ULN.
6. Serum creatinine = 1.5 x institutional ULN,
7. Patients not receiving anticoagulant medication who have an International
Normalized Ratio (INR) =1.5 and an Activated ProThrombin Time (aPTT) =1.5 x ULN.
The use of full-dose oral or parenteral anticoagulants is permitted as long as
the INR or APTT is within therapeutic limits (according to site medical standard)
and if the patient is on a stable dose of anticoagulants for at least two weeks
at the time of randomization.
8. Urine dipstick for proteinuria < 2+. If urine dipstick is =2+, 24-hours urine
must demonstrate =1 g of protein in 24 hours.
9. Normal blood pressure or adequately treated and controlled hypertension (systolic
BP = 140 mmHg and/or diastolic BP = 90 mmHg).
9. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
For France only: In France, a subject will be eligible for randomization in this study only
if either affiliated to, or a beneficiary of, a social security category
Exclusion Criteria:
1. Non-epithelial tumor origin of the ovary, the fallopian tube or the peritoneum (i.e.
germ cell tumors).
2. Ovarian tumors of low malignant potential (e.g. borderline tumors)
3. Patients with synchronous primary endometrial cancer unless both of the following
criteria are met:
1. stage < II,
2. Less than 60 years old at the time of diagnosis of endometrial cancer with stage
IA or IB grade 1 or 2, or stage IA grade 3 endometrioid adenocarcinoma OR = 60
years old at the time of diagnosis of endometrial cancer with stage IA grade 1or
2 endometrioid adenocarcinoma.
3. Patients with serous or clear cell adenocarcinoma or carcinosarcoma of the
endometrium are not eligible.
4. Other malignancy within the last 5 years except cervix or breast in situ carcinoma,
breast cancer = 3 years free of disease and treatment, type I stage I endometrial
cancer).
5. Patients receiving radiotherapy within 6 weeks prior to study treatment.
6. Major surgery within 4 weeks of starting study treatment or patients who have not
completely recovered from the effects of any major surgery. Core biopsy or other minor
surgical procedure, excluding placement of a vascular access device, within 7 days
prior to Day 1, Cycle 1
7. Previous allogeneic bone marrow transplant or previous solid organ transplantation.
8. Administration of other simultaneous chemotherapy drugs, any other anticancer therapy
or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial
treatment period (hormonal replacement therapy is permitted).
9. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-PD1,
or anti-PDL1 therapeutic antibodies or anti-CTLA 4.
10. Treatment with systemic immunostimulatory agents (including but not limited to
interferon-alpha (IFN-a) and interleukin-2 (IL-2) within 4 weeks or five half-lives of
the drug (whichever is shorter) prior to Cycle 1, Day 1
11. 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
1. The use of inhaled corticosteroids for chronic obstructive pulmonary disease,
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic
hypotension, and low-dose supplemental corticosteroids for adrenocortical
insufficiency are allowed.
2. Prophylactic anti-emetic corticosteroids will be avoided if possible in patients
treated with pegylated liposomal doxorubicin-carboplatin or
gemcitabine-carboplatin regimen. The use of corticosteroids is allowed as
premedication for paclitaxel-based regimen and/or premedication in case of
carboplatin hypersensitivity.
12. 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. Are eligible patients with:
1. a history of autoimmune hypothyroidism on a stable dose of thyroid replacement
hormone
2. controlled Type 1 diabetes mellitus on a stable insulin regimen
13. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic
organizing pneumonia), or evidence of active pneumonitis. Radiation pneumonitis in the
radiation field (fibrosis) detected on screening chest CT scan is permitted
14. Immunocompromised patients, e.g., patients who are known to be serologically positive
for human immunodeficiency virus (HIV). Patients with active hepatitis B (defined as
having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis
C.
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection
(defined as having a negative HBsAg test and a positive antibody to hepatitis B core
antigen [anti-HBc] antibody test) are eligible Patients positive for hepatitis C virus
(HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for
HCV RNA.
15. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
16. Administration of a live, attenuated vaccine within 4 weeks prior to Cycle 1, Day 1 or
anticipation that such a live attenuated vaccine will be required during the study.
Influenza vaccination should be given during influenza season only (example
approximately October to March in the Northern Hemisphere). Patients must not receive
live, attenuated influenza
17. Current or recent (within 10 days prior to randomization) chronic use of aspirin > 325
mg/day.
18. Prior history of hypertensive crisis (CTC-AE grade 4) or hypertensive encephalopathy.
19. Inadequately controlled HTN (defined as systolic blood pressure > 150 mmHg and/or
diastolic blood pressure > 100 mmHg on antihypertensive medications)
20. Clinically significant (e.g. active) cardiovascular disease, including:
1. Myocardial infarction or unstable angina within = 6 months of randomization,
2. New York Heart Association (NYHA) = grade 2 congestive heart failure (CHF),
3. Poorly controlled cardiac arrhythmia despite medication (patients with rate
controlled atrial fibrillation are eligible),
4. Peripheral vascular disease grade = 3 (e.g. symptomatic and interfering with
activities of daily living [ADL] requiring repair or revision)
21. Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or
family history of long QT syndrome.
22. Left ventricular ejection fraction defined by MUGA/ECHO below the institutional lower
limit of normal (only applicable for patients intended to be treated with pegylated
liposomal doxorubicin).
23. Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or
Sub-Arachnoids Hemorrhage (SAH) within 6 months prior to randomization.
24. History or evidence of hemorrhagic disorders within 6 months prior to randomization.
25. Evidence of bleeding diathesis or significant coagulopathy (in the absence of
coagulation).
26. 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.
27. History or evidence upon neurological examination of central nervous system (CNS)
disease, unless adequately treated with standard medical therapy (e.g. uncontrolled
seizures).
28. Significant traumatic injury during 4 weeks prior to randomization.
29. Non-healing wound, active ulcer or bone fracture. Patients with granulating incisions
healing by secondary intention with no evidence of facial dehiscence or infection are
eligible but require 3 weekly wound examinations.
30. History of VEGF therapy related abdominal fistula or gastrointestinal perforation.
31. Current, clinically relevant bowel obstruction, including sub-occlusive disease,
related to underlying disease.
32. Patients with evidence of abdominal free air not explained by paracentesis or recent
surgical procedure.
33. 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.
34. Women of childbearing potential (<2 years after last menstruation and not surgically
sterile) not willing to use highly-effective means of contraception (Appendix 1)
during the study and for 6 months after the last dose of study medication
35. Pregnant or lactating women.
36. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins.
37. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
ovary cells or to any component of the atezolizumab formulation.
38. Known hypersensitivity reaction or allergy to drugs chemically related to bevacizumab,
carboplatin, gemcitabine, paclitaxel, pegylated liposomal doxorubicin, or their
excipients that contraindicates the subject's participation
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