| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Efficacy of atezolizumab in combination with non-platinum based chemotherapy and bevacizumab versus the combination of a non-platinum based chemotherapy and bevacizumab in recurrent ovarian cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Efficacy of atezolizumab and bevacizumab in patients with recurrent ovarian cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016182 |
| E.1.2 | Term | Fallopian tube cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057529 |
| E.1.2 | Term | Ovarian cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Overall survival (OS), defined as the time from randomi-zation to death from any cause
Progression free survival (PFS) defined as the time from randomization to progressive disease (PD) or death, which-ever occurs earlier. PD is based on investigator assess-ment using the Response Evaluation Criteria in Solid Tu-mors (RECIST v1.1)
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|
| E.2.2 | Secondary objectives of the trial |
•QoL/PROs including predefined subgroups (symptomatic vs asymptomatic) and subdo-mains (EORTC C-30, OV28, PRO-CTCAE) and time until
• definitive deterioration (TUDD) including To determine the impact of atezolizumab versus placebo in combination with non-platinum-based chemotherapy + bevacizumab on patient-reported abdominal symptoms of OC, as measured by two items from the abdominal/GI scale of the EORTC QLQ-OV28
• To evaluate PROs of function and HRQoL associated with atezolizumab versus placebo in combination with non-platinum based chemotherapy + bevacizumab, as meas-ured by the functional and HRQoL scales of the EORTC QLQ-C30
• To evaluate overall response rate (ORR) and duration of response (DOR)
• Efficacy regarding OS, PFS, ORR/DOR depending onPD-L1 positivity defined by the VENTANA SP142 assay (negative: IC 0 versus positive IC: 1/2/3)
• To evaluate safety and tolerability of atezolizumab versus placebo in combination with non-platinum chemotherapy + bevacizumab. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. A washout period of at least 20 days after last bevacizumab treatment must be adhered.
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 admin-istration of study treatment:
-Hemoglobin ≥ 9.0 g/dl
-Absolute neutrophil count (ANC) ≥ 1.5 x 10E9/L
-Platelet count ≥ 100 x 10E9/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 Transam-inase (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 ran-domization
-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 het-erosexual inter-course) 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 out-comes questionnaires.
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|
| E.4 | Principal exclusion criteria |
1.Non-epithelial tumor origin of the ovary, the fallopian tube or the peritoneum
2.Ovarian tumors of low malignant potential
3.Malignancies other than ovarian cancer within 5 years prior to randomisation (..)
4.More than three prior systemic anticancer regimens; maintenance therapies are not calculated as separate line.
5.Prior systemic anticancer therapy within 28 days before randomization (except beva 20d).
6.Prior radiotherapy to the pelvis or the abdomen.
7.Administration of other simultaneous chemotherapy drugs, any other anticancer ther-apy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period (hormonal RT 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 (including but not limited to inter-feron-alpha and interleukin-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 (..) 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 obstructive pulmonary disease, mineral-ocorticoids (..)
12.Patients with a history of allergic reaction to IV contrast requiring steroid pre-treatment should have screening and subsequent tumor assessments performed using 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. (..)
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, or evidence 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, TIA or Sub-Arachnoids Hemorrhage within 6m prior to randomization
19.History or evidence of thrombotic or hemorrhagic disorders within 6m prior to randomization
20.History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain ...
21.History of autoimmune disease (...)
22.Any prior history of hypertensive crisis (CTCAE gr4) or hypertensive encephalopathy
23.Immunocompromised patients (...)
24.Persistent toxicities (≥ CTCAE gr2) ..
25.Severe infection requiring oral or IV antibiotics within 4 weeks prior to randomization ..
26.Current or recent (within 10d prior randomization) chronic use of aspirin > 325 mg/day
27.Clinically significant cardiovascular disease ..
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
30.Non-healing wound, active ulcer or bone fracture
31.History of bowel obstruction related to underlying disease, a history of abdominal 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 contraindicates 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall Survival (OS)
Progression-free Survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
at least 391 OS events have been observed
at least 547 PFS events should be observed in the same time |
|
| E.5.2 | Secondary end point(s) |
Quality of Life (QoL) and Patient Reported Outcome (PRO)
Evaluation of Overall Response Rate (ORR) and Duration of Response (DOR)
Efficacy regarding OS, PFS, ORR/DOR depending on PD-L1 positivity defined by the VENTANA SP142 assay (negative: IC 0 versus positive IC: 1/2/3)
Evaluation of Safety and Tolerability of Atezolizumab |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Quality of Life (QoL) and Patient Reported Outcome (PRO) every 4 weeks during the first 3 months, then every 12 weeks
Evaluation of Overall Response Rate (ORR) and Duration of Response (DOR) every 12 weeks until disease progression
Evaluation of Safety and Tolerability of Atezolizumab at every visit |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Paclitaxel, Pegylated Liposomal Docorubicin |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 200 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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