Status and phase
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About
This is a phase III, randomized, partially blinded, multicenter trial to evaluate the efficacy and safety of atezolizumab plus bevacizumab and chemotherapy compared to placebo plus bevacizumab and chemotherapy in patients with recurrent ovarian-, fallopian tube, or primary peritoneal cancer with 1st or 2nd relapse within 6 months after platinum based chemotherapy or 3rd relapse.
Full description
Approximately 550 patients will be randomized in a 1:1 ratio to the treatments as specified below:
Arm A: Chemotherapy + Bevacizumab + Placebo Arm B: Chemotherapy + Bevacizumab + Atezolizumab
Study treatment will continue until disease progression per RECIST v1.1, unacceptable toxicity, or patient or investigator decision to discontinue treatment. Atezolizumab/placebo, chemotherapy and bevacizumab may be discontinued for toxicity independently of each other in the absence of disease progression.
For each patient, chemotherapy (PLD or Paclitaxel weekly) will be selected by the investigator prior to randomization.
Recruitment to an individual chemotherapy cohort will be closed once 50% of patients are recruited to this cohort. In such case the remaining cohort will remain open for recruitment.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Patients with histologically diagnosed ovarian, fallopian tube, or primary peritoneal cancer
Relapsed disease
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
Measurable disease, evaluable disease in combination with GCIG CA-125 criteria, or histologically proven relapse/progression
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.
Availability of a representative archival FFPE tumor sample (preferable from primary diagnosis)
Patient has not progressed on the chosen/planned chemotherapy (PLD or Paclitaxel) in any prior line
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.
Females aged ≥ 18 years at signing at time of signing informed consent form
Signed written informed consent and ability to comply with the study protocol, in the investigator's judgement
Adequate hematological, renal and hepatic function within 28 days prior to first administration of study treatment:
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.
Estimated life expectancy of at least 3 months
ECOG performance status 0 - 1
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
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.
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.
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
Non-epithelial tumor origin of the ovary, the fallopian tube or the peritoneum (i.e. germ cell tumors)
Ovarian tumors of low malignant potential (e.g. borderline tumors)
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)
More than three prior systemic anticancer regimens; maintenance therapies (e.g. with bevacizumab, olaparib or niraparib) are not calculated as separate line.
Prior systemic anticancer therapy within 28 days before randomization (except bevacizumab: 20 days).
Prior radiotherapy to the pelvis or the abdomen.
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).
Prior treatment with anti-CD137 or immune checkpoint blockade therapies, anti-PD1, or anti-PD-L1 therapeutic antibodies or anti-CTLA 4
Prior randomization in AGO-OVAR 2.29.
Treatment with systemic immunostimulatory agents (in-cluding 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 longer) prior to cycle 1, day 1.
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.
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).
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
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.
Previous allogeneic bone marrow transplant or previous solid organ transplantation.
Current treatment with anti-viral therapy for HBV.
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
Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or Sub-Arachnoids Hemorrhage (SAH) within 6 months prior to randomization
History or evidence hemorrhagic disorders within 6 months prior to randomization
Patients are excluded if having a history or evidence of thrombosis as follows:
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
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:
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:
Any prior history of hypertensive crisis (CTCAE grade 4) or hypertensive encephalopathy.
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.
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.
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.
Current or recent (within 10 days prior randomization) chronic use of aspirin > 325 mg/day.
Clinically significant (e.g. active) cardiovascular disease, including:
For patients with PLD treatment: Left ventricular ejection fraction defined by ECHO below the institutional lower limit of normal
Evidence of bleeding diathesis or significant coagulopathy (in the absence of anticoagulation).
Non-healing wound, active ulcer or bone fracture.
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.
Patients with evidence of abdominal free air.
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
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
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.
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.
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).
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.
Primary purpose
Allocation
Interventional model
Masking
550 participants in 2 patient groups, including a placebo group
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Data sourced from clinicaltrials.gov
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