| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with late relapse of epithelial ovarien cancer, fallopian tube or peritoneal cancer treated with chemotherapy , bevacizumab and a anti PD-L1 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Determine the efficacy of atezolizumab in patients receiving a chemotherapy and bevacizumab to treat late relapse of ovarian cancer, fallopian tube or peritoneal 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 | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016180 |
| E.1.2 | Term | Fallopian tube cancer |
| 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 | 19.0 |
| 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 |
| The primary efficacy outcome measure is investigator determined progression-free survival (PFS1) as assessed using RECIST v1.1 |
|
| E.2.2 | Secondary objectives of the trial |
- Supportive secondary objectives
To determine the efficacy of atezolizumab compared to placebo on:
• Time from randomization to second subsequent therapy or death (TSST)
• Health-related Quality of Life (HRQoL) and patient reported outcomes (PROs) as measured by EORTC QLQ-C30 and OV28
• Overall survival (OS)
- Others secondary objectives
To determine the efficacy of atezolizumab compared to placebo on:
• Objective Response Rate (ORR) as assessed by RECIST v1.1 and irRECIST
• PFS1 as assessed per irRECIST
• Characterization of CA-125 tumor marker levels and their relation to tumor response and PFS1 as measured by RECISTv 1.1 and irRECIST
• Time from randomization to first subsequent therapy or death (TFST)
• Time from randomization to second progression (PFS2)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
I-1. Female Patients must be ≥18 years of age.
I-2. Signed informed consent and ability to comply with treatment and follow-up.
I-3. Patients with histologically confirmed non-mucinous epithelial ovarian cancer, primary peritoneal adenocarcinoma and / or fallopian-tube adenocarcinoma
I-4. Patients with known PD-L1 status on fresh mandatory 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 two 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.
I-5. Patients whose disease has relapsed more than 6 months from the last dose of platinum before randomization:
a) criterion for relapse can be according to RECIST v1.1, CA125 (GCIG) or clinical symptoms
b) 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.
I-6. Patients with one or 2 prior lines of chemotherapy. The last line of chemotherapy should have included platinum.
I-7. Availability at the study site of a representative FFPE tumor sample or at least 15 unstained slides from debulking surgery during front-line therapy
I-8. Patients must have normal organ and bone marrow function :
a) Haemoglobin ≥ 10.0 g/dL.
b) Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
c) Platelet count ≥ 100 x 109/L.
d) Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
e) 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.
f) Serum creatinine ≤ 1.5 x institutional ULN,
g) 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.
h) Urine dipstick for proteinuria < 2+. If urine dipstick is ≥2+, 24-hours urine must demonstrate ≤1 g of protein in 24 hours.
i) Normal blood pressure or adequately treated and controlled hypertension (systolic BP ≤ 140 mmHg and/or diastolic BP ≤ 90 mmHg).
I-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.
|
|
| E.4 | Principal exclusion criteria |
E-1. Non-epithelial tumor origin of the ovary, the fallopian tube or the peritoneum (i.e. germ cell tumors).
E-2. Ovarian tumors of low malignant potential (e.g. borderline tumors)
E-3. Patients with synchronous primary endometrial cancer unless both of the following criteria are met:
a) stage < II,
b) 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.
c) Patients with serous or clear cell adenocarcinoma or carcinosarcoma of the endometrium are not eligible.
E-4. Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS).
E-5. Patients receiving radiotherapy within 6 weeks prior to study treatment.
E-6.Major surgery within 4 weeks of starting study treatment or patients who have not completely recovered from the effects of any major surgery.
E-7. Previous allogeneic bone marrow transplant or previous solid organ transplantation.
E-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).
E-9. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti−PD1, or anti−PDL1 therapeutic antibodies or anti-CTLA 4.
E-10. Treatment with systemic immunostimulatory agents
E-11. Treatment with systemic corticosteroids or other systemic immunosuppressive médications.
a) 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.
b) 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.
E-12. History of autoimmune disease
E-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
E-14. Immunocompromised patients,
E-15. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
E-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.
E-17. Current or recent (within 10 days prior to randomization) chronic use of aspirin > 325 mg/day.
E-18. Prior history of hypertensive crisis (CTC-AE grade 4) or hypertensive encephalopathy.
E-19. Inadequately controlled HTN
E-20. Clinically significant (e.g. active) cardiovascular disease, including:
a) Myocardial infarction or unstable angina within ≤ 6 months of randomization,
b) New York Heart Association (NYHA) ≥ grade 2 congestive heart failure (CHF),
c) Poorly controlled cardiac arrhythmia despite medication (patients with rate controlled atrial fibrillation are eligible),
d) Peripheral vascular disease grade ≥ 3 (e.g. symptomatic and interfering with activities of daily living [ADL] requiring repair or revision)
E-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.
E-22. Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or Sub-Arachnoids Hemorrhage (SAH) within 6 months prior to randomization.
E-23. History or evidence of hemorrhagic disorders within 6 months prior to randomization.
E-24. Evidence of bleeding diathesis or significant coagulopathy (in the absence of coagulation).
E-25. History or clinical suspicion of brain metastases or spinal cord compression.
E-26. Significant traumatic injury during 4 weeks prior to randomization.
E-27. History of VEGF therapy related abdominal fistula or gastrointestinal perforation.
E-28. Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease.
E-29. Women of childbearing potential (<2 years after last menstruation and not surgically sterile) not willing to use highly-effective means of contraception during the study and for 3 months after the last dose of study medication
E-30. Pregnant or lactating women.
E-31.History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression free-survival (PFS1).
PFS1 is defined as the time from randomization until the date of the first objective radiological disease progression according to investigator assessment of RECIST version 1.1 or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized study treatment or receives another anti-cancer therapy prior to progression |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
278 events observed for the primary analysis.
Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST assessment. |
|
| E.5.2 | Secondary end point(s) |
Secondary supportive objectives
To determine the efficacy of atezolizumab compared to placebo on:
• Time from randomization to second subsequent therapy or death (TSST)
• Health-related Quality of Life (HRQoL) and patient reported outcomes (PROs) as measured by EORTC QLQ-C30 and OV28
•Overall survival (OS)
Others secondary objectives
To determine the efficacy of atezolizumab compared to placebo on:
• Objective Response Rate (ORR) as assessed by RECIST v1.1 and irRECIST
• PFS1 as assessed per irRECIST
• Characterization of CA-125 tumor marker levels and their relation to tumor response and PFS1 as measured by RECISTv 1.1 and irRECIST
• Time from randomization to first subsequent therapy or death (TFST)
• Time from randomization to second progression (PFS2)
Others secobdary objectives
To determine the efficacy of atezolizumab compared to placebo in the PD-L1-ve and PD-L1 +ve subgroups
To assess the safety and tolerability of atezolizumab compared to placebo
To evaluate the impact of treatment and disease on resource use as measured by different criteria including EuroQoL 5 Dimension (EQ-5D) questionnaire
Exploratory objectives
1. To explore pre-planned subgroups analyses of efficacy (PFS) based on relevant potential prognostic factors, including stratification factors, as well as on the performance or not of secondary cytoreductive surgery.
2. To evaluate the relationship between the expression of PD-L1, tumor mutational load and intraepithelial TILs with ORR and PFS.
3. To assess immune-related and other potential predictive and prognostic exploratory biomarkers in fresh/archival tissue and blood and their association with disease status and/or efficacy as defined by ORR and PFS.
4. To evaluate the relationship between PD-L1, TILs and biomarker status in archival tissue and in fresh tumor specimens.
5. To evaluate the utility of biopsy at the time of apparent disease progression to distinguish apparent increases in tumor volume related to immunomodulatory activity of atezolizumab (i.e., pseudoprogression/tumor immune infiltration) from true disease progression as determined by confirmatory CT scan for disease progression and PFS.
6. To explore whether resistance mechanisms to atezolizumab plus bevacizumab versus placebo plus bevacizumab alone can be identified through analysis of tumor and blood samples – archival tumor, fresh tumor biopsy and blood sample at baseline (mandatory), tumor biopsy and blood sample on progression (optional).
7. To collect and store ctDNA (according to each country’s local and ethical procedures) for future exploratory research into genes/genetic variation that may influence response (i.e., distribution, safety, tolerability and efficacy) to study treatments
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- This first interim safety analysis will be performed after the first 45 patients had received 2 cycles of treatment
- 278 events observed for the primary analysis.
- The IDMC will meet on a regular basis and will be responsible for independently evaluation of the safety for the patients. IDMC will make recommendations concerning the conduct of the trial
- No interim efficacy analysis will be planned during the trial |
|
| 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 | Yes |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
-Quality of life
- Biomarkers |
|
| 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 | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 40 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 98 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belgium |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Israel |
| Italy |
| Norway |
| Spain |
| Sweden |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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