Atezolizumab With Bevacizumab and Chemotherapy vs Bevacizumab and Chemotherapy in Early Relapse Ovarian Cancer

  • STATUS
    Recruiting
  • End date
    Jul 1, 2022
  • participants needed
    664
  • sponsor
    AGO Research GmbH
Updated on 24 January 2021

Summary

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.

Description

Approximately 664 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.

Details
Condition Recurrent Ovarian Carcinoma, Recurrent Ovarian Cancer
Treatment bevacizumab, placebos, Chemotherapy, Atezolizumab
Clinical Study IdentifierNCT03353831
SponsorAGO Research GmbH
Last Modified on24 January 2021

Eligibility

Yes No Not Sure

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
Patient agrees and is able to provide a recent tumor biopsy (not older than 3 months) or agrees and has a tumor lesion amenable for taking a new tumor biopsy
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
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
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-) 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 of thrombotic or hemorrhagic disorders within 6
months prior to randomization
\. 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, Sjgren's syndrome, Guil-lain-Barr 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 22. Any prior history of hypertensive crisis (CTCAE grade 4) or hypertensive encephalopathy. 23. 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
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 28. For patients with PLD treatment: Left ventricular ejection fraction defined by ECHO below the institutional lower limit of normal 29. Evidence of bleeding diathesis or significant coagulopathy (in the absence of anticoagulation). 30. Non-healing wound, active ulcer or bone fracture. 31. 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. 32. Patients with evidence of abdominal free air. 33. 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 34. 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 35. 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. 36. 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. 37. Pregnancy, lactation, or intention to become pregnant during the study or within 5 months after the last dose of atezolizumab/placebo
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