| Eligibility |
Inclusion Criteria:
1. Patients with histologically diagnosed ovarian, fallopian tube, or primary peritoneal
cancer
2. Relapsed disease
3. Patients with up to three prior therapies. In patients with 1 or 2 prior treatment
lines, the treatment free interval after platinum has to be less than 6 months; in
addition patients with three prior lines of chemotherapy who are not considered for
platinum-containing chemotherapy lines are also eligible
4. Measurable disease, evaluable disease in combination with GCIG CA-125 criteria, or
histologically proven relapse/progression
5. Mandatory de novo tumor biopsy (not older than 3 months) sent to central laboratory as
formalin-fixed, paraffin-embedded (FFPE) sample for determination of PDL1 status prior
to randomization for stratification.
6. Availability of a representative archival FFPE tumor sample (preferable from primary
diagnosis)
7. Patient has not progressed on the chosen/planned chemotherapy (PLD or Paclitaxel) in
any prior line
8. Patients previously treated with bevacizumab are eligible, with the exclusion of those
patients that has suspended bevacizumab for more than 2 subsequent cycles or
permanently discontinued bevacizumab during their previous treatment due to toxicity.
9. Females aged = 18 years at signing at time of signing informed consent form
10. Signed written informed consent and ability to comply with the study protocol, in the
investigator's judgement
11. Adequate hematological, renal and hepatic function within 28 days prior to first
administration of study treatment:
- Hemoglobin = 9.0 g/dL
- Absolute neutrophil count (ANC) = 1.5 x 10xE^9/L
- Platelet count = 100 x 10xE^9/L
- Total bilirubin = 1.5 x institutional upper limit of normal (ULN)
- 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 case of liver metastases
values must be = 5 x ULN
- Serum creatinine = 1.5 x institutional ULN
- Patient not receiving anticoagulant medication who has 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). If the patient is on oral anticoagulants, dose has to be stable for at
least two weeks at the time of randomization
- Urine dipstick for proteinuria < 2+. If urine dipstick is = 2+, 24-hours urine
must demonstrate = 1 g of protein in 24 hours.
12. Patients must have adequately controlled blood pressure (BP), with a systolic BP of =
140 mmHg and diastolic BP of = 90 mmHg for eligibility. Patients must have a BP of =
140/90 mmHg taken in the clinic setting by a medical professional within 2 weeks prior
to starting study.
13. Estimated life expectancy of at least 3 months
14. ECOG performance status 0 - 1
15. Negative urine or serum pregnancy test within 7 days of study treatment in women of
childbearing potential (WOCBP), confirmed prior to treatment on day 1
16. For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use a contraceptive method with a failure rate of < 1%
per year during the treatment period and for at least 5 months after administration of
the last dose of atezolizumab/placebo and 6 months after the last dose of bevacizumab,
paclitaxel, or PLD, whichever is later.
17. For countries where this will apply to: a patient will be eligible for randomization
in this study only, if either affiliated to, or a beneficiary of a social security
category.
18. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other study procedures, that include the completion of patient-reported
outcomes questionnaires.
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. Malignancies other than ovarian cancer within 5 years prior to randomisation, with the
exception of those with a negligible risk of metastasis or death (e.g., 5-year OS rate
> 90%) and treated with expected curative outcome (such as adequately treated
carcinoma in situ of the cervix, non melanoma skin carcinoma, ductal carcinoma in
situ, or Stage I uterine cancer)
4. More than three prior systemic anticancer regimens; maintenance therapies (e.g. with
bevacizumab, olaparib or niraparib) are not calculated as separate line.
5. Prior systemic anticancer therapy within 28 days before randomization (except
bevacizumab: 20 days).
6. Prior radiotherapy to the pelvis or the abdomen.
7. 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 thera-py is permitted).
8. Prior treatment with anti-CD137 or immune checkpoint blockade therapies, anti-PD1, or
anti-PD-L1 therapeutic antibodies or anti-CTLA 4
9. Prior randomization in AGO-OVAR 2.29.
10. Treatment with systemic immunostimulatory agents (in-cluding 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 longer) prior to cycle 1, day 1.
11. Treatment with systemic corticosteroids or other systemic immunosuppressive
medications (including but not limited to prednisone, dexamethasone,
cyclophos-phamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis
factor [TNF] agents) within 2 weeks prior to cycle 1, day 1, or anticipated
requirement for systemic immunosuppressive medications during the trial.
The use of inhaled corticosteroids for chronic obstruc-tive pulmonary disease,
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension,
and low-dose supplemental corticosteroids for adrenocortical insufficiency are
allowed.
12. Patients with a history of allergic reaction to IV contrast requiring steroid
pre-treatment should have screening and subsequent tumor assessments performed using
magnetic resonance imaging (MRI).
13. 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 or
within 5 months after the last dose of atezolizumab/placebo. Influenza vaccination
should be given during influenza season only. Patients must not receive live,
attenuated influenza vaccination
14. Major surgery within 4 weeks of starting study treatment or patient who has not
completely recovered from the effects of any major surgery. Core biopsy or other minor
surgical procedure within 7 days prior to day 1, cycle 1 is permitted.
15. Previous allogeneic bone marrow transplant or previous solid organ transplantation.
16. Current treatment with anti-viral therapy for HBV.
17. History of idiopathic pulmonary fibrosis (including pneumonitis), organizing pneumonia
(i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evi-dence of
active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the
radiation field (fibrosis) detected on screening chest CT scan is permitted
18. Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or
Sub-Arachnoids Hemorrhage (SAH) within 6 months prior to randomization
19. History or evidence hemorrhagic disorders within 6 months prior to randomization
20. Patients are excluded if having a history or evidence of thrombosis as follows:
- Any Grade 4 thrombosis
- Arterial thrombosis within 6 months prior to ran-domization
- Grade = 3 venous thrombosis within 3 months prior to randomization Patients with
central venous access thrombosis are eligi-ble.
21. 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
sus-pected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to
randomization) in case of sus-pected spinal cord compression
22. History of autoimmune disease, including but not limited to dermatomyositis,
myasthenia gravis, myositis, auto-immune hepatitis, systemic lupus erythematosus,
rheu-matoid arthritis, inflammatory bowel disease, vascular thrombosis associated with
anti-phospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome,
Guil-lain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
Except patients with:
- a history of autoimmune hypothyroidism on a stable dose of thyroid replacement
hormone
- controlled type 1 diabetes mellitus on a stable insulin regimen
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are met:
- Rash must cover < 10% of body surface area
- Disease is well controlled at baseline and requires only low-potency topical
corticosteroids
- No occurrence of acute exacerbations of the underlying condition requiring
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents,
oral calcineurin inhibitors, or high potency or oral corticosteroids within the
previous 12 months
23. Any prior history of hypertensive crisis (CTCAE grade 4) or hypertensive
encephalopathy.
24. 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 re-solved 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.
25. Persistent toxicities (= CTCAE grade 2) with the exception of alopecia, caused by
previous cancer treatment. Neurotoxicity CTCAE grade 2 is permitted in case the
patient is planned for PLD treatment.
26. Severe infection requiring oral or IV antibiotics within 4 weeks prior to
randomization, including but not limited to active tuberculosis or hospitalization for
complications of infection, bacteremia, or severe pneumonia. Patients receiving
prophylactic antibiotics (e.g., to prevent urinary tract infection or chronic
obstructive pulmonary disease exacerbation) are eligible for the study.
27. Current or recent (within 10 days prior randomization) chronic use of aspirin > 325
mg/day.
28. Clinically significant (e.g. active) cardiovascular disease, including:
- Myocardial infarction or unstable angina pectoris within = 6 months of
randomization
- New York Heart Association (NYHA) = grade 2 congestive heart failure (CHF)
- Poorly controlled cardiac arrhythmia despite medica-tion (patients with rate
controlled atrial fibrillation are eligible)
- Peripheral vascular disease grade = 3 (e.g. symptomatic and interfering with
activities of daily living [ADL] requiring repair or revision)
- Resting ECG with QTc >470 msec or family history of long QT syndrome
29. For patients with PLD treatment: Left ventricular ejection fraction defined by ECHO
below the institutional lower limit of normal
30. Evidence of bleeding diathesis or significant coagulopathy (in the absence of
anticoagulation).
31. Non-healing wound, active ulcer or bone fracture.
32. History of bowel obstruction (including subocclusive disease) related to underlying
disease, a history of ab-dominal fistula, GI perforation, or intra-abdominal abscess,
or evidence of deep infiltration of the bowel by pelvic examination or on computed
tomography, or clinical symptoms of bowel obstruction.
33. Patients with evidence of abdominal free air.
34. Evidence of any other disease, metabolic dysfunction, physical examination finding or
laboratory finding giving reasonable suspicion of disease or condition that
contraindicates the use of an investigational drug or puts the patient at high risk
for treatment related complications
35. Known hypersensitivity or allergy to drugs containing Chinese hamster (CHO) ovary
cells or history of severe allergic, anaphylactic, or other hypersensitivity reactions
to chimeric or humanized antibodies or fusion proteins
36. Known hypersensitivity reaction or allergy to drugs chemically related to bevacizumab,
paclitaxel, pegylated liposomal doxorubicin, or their excipients that contra-indicates
the subject's participation.
37. Patients considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled infection. This
includes also any psychiatric disorder that prohibits obtaining informed consent.
38. Pregnancy, lactation, or intention to become pregnant during the study or within 5
months after the last dose of atezolizumab/placebo as well as breastfeeding women or
intended to breastfeed during the study and up to 6 months after treatment with
paclitaxel, bevacizumab and pegylated liposomal doxorubicin (PLD).
39. For France only: Patients deprived of their liberty by judicial or administrative
decision and patients under a legal protection measure or unable to express their
consent.
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