| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent ovarian, tubal or peritoneal cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033130 |
| E.1.2 | Term | Ovarian cancer NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
| Determine whether the addition of atezolizumab to carboplatin-based chemotherapy followed by maintenance niraparib improves progression-free survival (PFS) compared to placebo combined with carboplatin-based chemotherapy followed by maintenance niraparib, in patients with relapsed epithelial ovarian, fallopian tube, or peritoneal cancer after a platinum treatment free interval (TFIp) of at least 6 months (platinum-sensitive). |
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| E.2.2 | Secondary objectives of the trial |
- Evaluate overall survival
- Evaluate time from randomization to first subsequent therapy or death (TFST)
- Evaluate time from randomization to second subsequent therapy or death (TSST)
- Evaluate time from randomization to second progression or death (PFS2)
- Assess the safety and tolerability of atezolizumab treatment compared to placebo treatment
- Determine the impact of atezolizumab versus placebo on patient-reported abdominal symptoms of ovarian cancer.
- Evaluate patient-reported outcomes of function and health related quality of life associated with atezolizumab versus placebo
- Evaluate the ORR
- Evaluate the duration of response
- Evaluate the PFS
- Evaluate the efficacy of atezolizumab versus placebo according to BRCA status
- To evaluate the efficacy of atezolizumab compared to placebo in the PD-L1 negative and PD-L1 positive subgroups |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
- Evaluate PROs of disease and/or treatment-related symptoms associated with atezolizumab versus placebo, as measured by the EORTC QLQ-C30 and QLQ-OV28
- Evaluate any treatment burden patients may experience in association with atezolizumab versus placebo, as measured by a single item (from GP5: "I am bothered by side effects of treatment") from the physical wellbeing subscale of the FACT-G Quality of Life instrument
- Evaluate and compare between treatment arms patients' health utility as measured by EQ-5D-5L and EQ-5D VAS to generate utility scores for use in economic models for reimbursement
- Explore the association of PD-L1 expression and other immune biomarkers with clinical outcomes
- Explore biomarkers that may be predictive of the response to atezolizumab, prognostic of the disease or associated to the anti-tumor effect of treatmet (pharmacodynamic)
- Explore the effect of antibiotic (ATB) use on the efficacy of atezolizumab. The use of ATB might alter the composition of the gut microbiome causing dysbiosis and this may impact on atezolizumab activity.
-To evaluate the efficacy of atezolizumab vs placebo according to previous use of PARP inhibitors in front line.
-To explore the correlation between PD-L1 expression status in archival tissue and in “de novo” tumor specimens (to be determined upon further consideration and agreement).
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|
| E.3 | Principal inclusion criteria |
1. Patients ≥ 18 years old
2. Life expectancy ≥3 months
3. Signed informed consent and ability to comply with treatment and follow-up
4. Histologically confirmed diagnosis (cytology alone excluded) of high- grade serous or endometrioid ovarian, primary peritoneal or tubal carcinoma. In addition, mixed histologies with predominat high grade serous or endometrioid, or undifferentiated adenocarcinoma of the ovary are allowed
5. BRCA mutational status is known (germline or somatic)
6. Relapsed disease more than 6 months after the last platinum dose:
7. No more than 2 prior lines of chemotherapy are allowed, and the last one must contain a platinum-based regimen
8. At least one measurable lesion to assess response by RECIST v1.1 criteria.
9. Mandatory de novo tumor biopsy (collected within 3 months prior to randomization) for PD-L1 status determination for randomization. The inclusion of patients with non informative tissue PD-L1 status will be capped to 10% of the whole study population:
-If the mandatory de novo biopsy is technically not possible or failed to produce enough representative tumor tissue, a FFPE sample from archival tissue may be acceptable after approval of the sponsor.
-Bone metastases, fine needle aspiration, brushing, cell pellet from pleural effusion, or ascites or lavage are not acceptable.
10. Two additional tumour samples are needed: Archival tumor sample for exploratory PD-L1 testing in archival tissue and archival or ”de novo” tissue sample for biomarkers.
11. Performance status determined by ECOG score of 0-1
12. Patients must have normal organ and bone marrow function:
- Haemoglobin ≥10.0 g/dL
- Absolute neutrophil count (ANC) ≥1.5 x 109/L
- Lymphocyte count ≥0.5 × 109/L
- Platelet count ≥100 x 109/L
- Total bilirubin ≤1.5 x institutional upper limit of normal (ULN)
- Serum albumin ≥2.5 g/dL
- Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤2.5 x ULN, unless liver metastases are present in which case they must be ≤5 x ULN
- Serum creatinine ≤1.5 x institutional ULN or calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation
- Patients not receiving anticoagulant medication must have an International Normalized Ratio (INR) ≤1.5 and an Activated ProThrombin Time (aPTT) ≤1.5 x ULN.
13. Negative Test Results for Hepatitis
14. Toxicities related to previous treatments must be recovered to < grade 2 (with the exception of alopecia)
15. Examples of contraceptive methods with a failure rate of <1% per year include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (in-travaginal, transdermal*), progestogen-only hormonal contraception associated with inhibition of ovulation (injectable, implantable*), intrauterine device (IUD), intrauterine hormone-releasing sys-tem (IUS), bilateral tubal occlusion/ligation, vasectomized partner, sexual abstinence.
*Due to a reasonable frequency of emesis and diarrhea under the planned therapy, oral contraceptives are not considered “highly effective”
16. Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment.
17. Participant must agree to not breastfeed during the study or for 180 days after the last dose of study treatment. |
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| E.4 | Principal exclusion criteria |
1. Non-epithelial tumor of the ovary, fallopian tube or peritoneum
2. Ovarian tumors of low malignant potential or low grade
3. Other malignancy within the last 5 years except curatively treated non-melanoma skin cancer, in situ cancer of the cervix and ductal carcinoma in situ
4. Major surgery or patients who have not completely recovered from the effects of any major surgery at randomization
5. Core biopsy or other minor surgical procedure within 7 days prior to Day 1 Cycle 1
6. Administration of other chemotherapy drugs, anticancer therapy or antineoplastic hormonal therapy, or treatment with other investigational agents or devices within 28 days prior to randomization, or within a time interval less than at least 5 half-lives of the investigational agent
7. Palliative radiotherapy within 6 weeks prior to randomization or patients who have not completely recovered (Grade ≥ 2) from the effects of previous radiotherapy
8. Current or recent chronic use of aspirin or clopidogrel
9. Clinically significant cardiovascular disease
10. Resting ECG with QTc >470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
11. Left ventricular ejection fraction defined by MUGA/ECHO below the institutional lower limit of normal
12. History or clinical suspicion of brain metastases or spinal cord compression
13. History or evidence upon neurological examination of central nervous system disorders
14. Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease
15. Uncontrolled tumor-related pain
16. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
17. Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
18. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment related complications
19. Pregnant or lactating women
20. Simultaneously receiving therapy in any interventional clinical trial
21. Prior treatment with CD137 agonists or immune checkpoint stimulating or blockade therapies, such as anti−PD1, anti−PDL1 or anti-CTLA4 therapeutic antibodies
22. Treatment with systemic immunostimulatory agents
23. Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to Cycle 1 Day 1
24. History of autoimmune disease: myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis or glomerulonephritis.
25. History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia or evidence of active pneumonitis
26. Immunocompromised patients ( e.g. HIV)
27. Signs or symptoms of infection within 4 weeks prior to Cycle 1 Day 1
28. Active tuberculosis
29. Administration of a live, attenuated vaccine
30. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
31. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or to any component of the atezolizumab formulation or allergy to any of the other drugs included in the protocol or their solvents
32. Patient has received prior treatment with a PARP inhibitor in the recurrent setting or has participated in a study where any treatment arm included administration of a PARP inhibitor in the recurrent setting, unless the patient is unblinded and there is evidence of not having received a PARP inhibitor. Patients that received PARP inhibitor as front line are eligible for the study. The duration of exposure to PARPi following front line therapy needs to be ≥18 months for BRCA mutated patients and ≥ 12 months for BRCA wild type patients.
33. Patient has had any known ≥Grade 3 hematological toxicity anemia, neutropenia or thrombocytopenia due to prior cancer chemotherapy that persisted >4 weeks and was related to the most recent treatment
34. Patient has any known history or current diagnosis of MDS or AML
35. Previous allogeneic bone marrow transplant or previous solid organ transplantation
36. Patient has a condition (such as transfusion dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that might confound the study results or interfere with the patient’s participation for the full duration of the study treatment
37. Participant has any known hypersensitivity to niraparib components or excipients |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-free survival (PFS) from randomization until progression based on investigator assessment determined by RECIST (Version 1.1)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PFS is the period from study entry (day of randomization) until disease progression, death or date of last contact. Progression will be based on tumor assessment made by the investigators according to the RECIST v1.1 criteria. |
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| E.5.2 | Secondary end point(s) |
- Overall survival (OS), defined as the observed length of life from entry into the study (day of randomization) to death from any cause, or the date of last contact
- Time from randomization to first subsequent therapy or death (TFST)
- Time from randomization to second subsequent therapy or death (TSST)
- Time from randomization to second progression or death (PFS2)
- Frequency and severity of adverse events as assessed by CTCAE version 5.0 for the regimens administered on this study
- Clinically-meaningful improvement in patient-reported abdominal pain or bloating, defined as a 10-point decrease from the baseline score on either of the two items of the EORTC QLQ-OV28 abdominal/GI symptom scale (items 31 and 32)
- Clinical improvement, remaining stable, or deterioration in patient-reported function and HRQoL, defined as a 10-point increase, changes within 10 points, and a 10-point decrease, respectively, from the baseline score on each of the functional (physical, role, emotional, and social) and global health status/HRQoL scales of EORTC QLQ-C30
- Objective Response Rate (ORR) as assessed by RECIST v1.1 during the chemotherapy phase and during the maintenance phase
- Duration of response (DOR) by RECIST v1.1
- PFS from start of the maintenance phase (period from start of maintenance treatment until disease progression, death or date of last contact) assessed by the investigator according to RECIST v1.1 criteria, in all patients receiving maintenance treatment as well as in the subgroup of patients with CR/PR of SD after completing chemotherapy
- Relationship of primary and secondary endpoint outcomes with BRCA mutational status and other stratification factors
- Mean and mean changes from the baseline score in disease and/or treatment-related symptoms by cycle and between treatment arms as assessed by all symptom items and/or scales of EORTC QLQ-C30 and QLQ-OV28
- Proportion of patients reporting each response option at each assessment timepoint by treatment arm for item GP5 from the FACT-G instrument
- Health utility scores of the EuroQoL 5 Dimension, 5 Level Questionnaire (EQ-5D-5L). European Quality of Life Visual Analogue Scale (EQ-VAS)
- Relationship between tumour immune-related or disease type-related biomarkers (including but not limited to mutational burden, PD-L1, TILs and cluster of differentiation [CD]8) in tumour tissues or blood samples, and clinical outcomes
- Relationship between certain exploratory biomarkers (e.g. circulating cell-free DNA, proteins and cytokines) assessed from plasma before and during/after treatment, and clinical outcomes
- Relationship between ATB use within 2 month before and 1 month after the first study administration with atezolizumab efficacy as measured by PFS and OS.
- Relationship between previous use of PARP inhibitors in front line and clinical outcomes.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- OS: length of life from entry into the study to death
- TFST: from randomization to first subsequent therapy or death
- TSST: from randomization to second subsequent therapy or death
- PFS2: time from randomization to second progression or death
- Averse events assessed every cycle
- ORR and DOR assessed during the chemotherapy phase and during the maintenance phase
- PFS: from start of the maintenance phase
- Mean and mean changes from the baseline score in disease and/or treatment-related symptoms assessed by EORTC QLQ-C30 and QLQ-OV28
- Assessment of plasma before and during/after treatment, and clinical outcomes
- Relationship between ATB use within 2 months before and 1 month after the first study administration |
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| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | 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 | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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
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| 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 | |
| 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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