| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 | 10051938 |
| E.1.2 | Term | Ovarian adenocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| 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 |
The primary objective of the study is to evaluate the efficacy and safety of 3 different treatments arms (bevacizumab alone, atezolizumab-bevacizumab combination with ASA and atezolizumab-bevacizumab combination with placebo) in advanced recurrent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer patients in order to select the optimal treatments for further development in phase III.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to:
♦assess the biological activity and immunological effects of each treatment in the tumor microenvironment and in the peripheral blood
♦assess the effect of treatment on disease control and overall survival |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
♦ Recurrent, histologically proven, platinum-resistant, epithelial ovarian cancer, fallopian tube and primary peritoneal cancer in advanced or metastatic stage. Histological diagnosis by image guided biopsy, laparoscopy or laparotomy. Tumors diagnosed on cytology only and borderline tumors (i.e. low malignant potential) are excluded.
♦ Platinum-resistant cancer is defined as disease that responded to platinum-based chemotherapy but with documented recurrence between 28 days and six months of completing this therapy
♦ At least one lesion accessible to biopsy without putting patient at risk
♦ Prior systemic (chemotherapy, hormonal therapy, biologic agents, and/or vaccines) or radiation treatment is allowed under following conditions:
♦ No prior treatment with Hyperthermic intraperitoneal chemotherapy (HIPEC)
♦ Systemic anti-tumoral treatment: wash-out period of 21 days prior to the first study treatment
♦ Any number of platinum-based chemotherapy lines are allowed but a maximum of 2 previous non-platinum containing lines
♦ Prior treatment with bevacizumab or other targeted agents against VEGF or VEGF receptor is allowed, but at least 18 weeks must have elapsed since their last administration
♦ Patients with ≤ 2 previous treatment lines must have been previously exposed to bevacizumab or other targeted agents against VEGF or VEGF receptor
♦ No current, recent (within 4 weeks of randomization), or planned participation in an experimental drug study
♦ Recovery from any toxic effects of prior therapy to ≤ Grade 1 per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.0) except fatigue or alopecia.
♦ Radiation therapy: recovery period of 14 days prior to the first study treatment; exception: single fraction radiotherapy with the indication of pain control and no prior radiation to the pelvis
♦ Age ≥18 years
♦ WHO PS: 0-2 for patients having received no more than two previous lines of therapy. WHO PS: 0-1 for patients having received >2 previous lines of therapy
♦ Life expectancy of ≥ 12 weeks
♦ Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 14 days prior to randomization:
♦ WBC counts > 2.5 x 10^9/L and < 15.0 x 10^9/L and ANC ≥ 1.5 x 10^9/L cells/µL (without granulocyte colony-stimulating factor support within 2 weeks prior to randomization), Lymphocyte count 0.5 x 10^9/L , Platelet count ≥ 100 x 10^9/L (without requiring transfusion within 1 week prior to randomization), Hemoglobin > 9.0 g/dL (Patients may be transfused to meet the hemoglobin criterion)
♦ AST, ALT, and alkaline phosphatase ≤ 2.5 x ULN, with the following exceptions:
♦ Patients with documented liver metastases: AST and ALT ≤ 5 x ULN
♦ Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5 x ULN
♦ Serum total bilirubin ≤ 1.5 x ULN
♦ Patients with suspicion of Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled.
♦ Adequate synthetic liver function with PT or INR and aPTT ≤ 1.5 x ULN and serum albumin > 25 g/l
♦ Creatinine clearance estimation: ≥ 40 ml/min/1.73m2 on the basis of the Chronic Kidney Disease Epidemiology Collaboration formula
♦ Estimated glomerular filtration rate = 141 x min(SCr/k,1)α x max(SCr/k,1) - 1.209 x 0.993 Age x 1.018 [if female] x [1.159 if Black] where SCr is serum creatinine (mg/dL), k 0.7 for female and 0.9 for males, α is - 0.329 for females and -0.411 for males, min indicates the minimum of SCr/k or 1, and max is the maximum of SCr/k or 1.
♦ Women of childbearing potential (WOCP: defined as a sexually mature woman who 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally post-menopausal (amenorrhoea following cancer therapy does not rule out childbearing potential) for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months)) must:
♦ Have a negative serum pregnancy test within 7 days prior to randomization.
♦ Agree to remain sexually abstinent, have a partner who is sterile (i.e., vasectomy), or use two medically effective methods of contraception during dosing and through 6 months after last study treatment. An effective method is the combination of the following (a+b): a. Hormonal method eg, birth control pills; b. Placement of an intrauterine device (IUD) or intrauterine system (fUS), barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/ gel/film/ cream/vaginal suppository. This requirement should be followed from screening through 6 months after last study treatment.
♦ During treatment: Patient should agree to urine pregnancy test to be performed before each treatment;
♦ Agree to discontinue treatment in case of pregnancy or positive pregnancy test.
♦ Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. |
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| E.4 | Principal exclusion criteria |
♦ Uncontrolled hypercalcemia [> 1.5 mmol/L (4.8 mg/dL) ionized calcium, or Total Ca > 3 mmol/L (12 mg/dL) or corrected serum calcium > ULN] or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
♦ Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible.
♦ Symptomatic brain or leptomeningeal disease; any brain metastases must be stable for at least 6 months
♦ Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
♦ Significant cardiovascular disease, such as:
♦ Inadequately controlled hypertension (defined as systolic blood pressure 150 mm Hg and/or diastolic blood pressure 100 mm Hg despite intensive medical management) or prior history of hypertensive crisis or hypertensive encephalopathy. Anti-hypertensive therapy is allowed.
♦ New York Heart Association Class II or greater congestive heart failure and history of myocardial infarction or unstable angina within 6 months prior to randomization.
♦ Significant vascular disease including stroke, transient ischemic attack, aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis within 6 months prior to randomization.
♦ Use of acetylsalicylic acid, NSAIDs or other COX-2 inhibitors that cannot be stopped at baseline and for the whole duration of the study. Occasional use (i.e. no more than 5 times/doses per (calendar) month) is allowed.
♦ Hypersensitivity to the active ingredient acetylsalicylic acid or any of the excipients, hypersensitivity to Chinese hamster ovary (CHO) cell products or other recombinant human or humanised antibodies or fusion proteins.
♦ Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation) and current or recent (within 10 days prior to randomization) use of dipyridamole, ticlopidine, clopidogrel, cilostazol, prasugrel, or ticagrelor; or use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose
♦ Prophylactic anticoagulation for the patency of venous access devices is allowed, provided the activity of the agent results in PT or an INR < 1.5 x ULN and aPTT is within normal limits within 1 week prior to randomization.
♦ Prophylactic or therapeutic use of low molecular-weight heparin (e.g., enoxaparin) is allowed.
♦ Obvious signs of, or risks for gastrointestinal fistula formation or perforation, such as
♦ History of bowel obstruction, including sub- occlusive disease, related to the underlying disease and history of abdominal fistula, tracheoesophageal fistula, gastrointestinal perforation or intra-abdominal abscess.
♦ Clinical symptoms of recent bowel obstruction or paralytic ileus, but excluding postoperative (within 4 weeks after abdominal surgery), or evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan
♦ Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture. Surgery (including open but not core biopsy) within 4 weeks prior to randomization, or anticipation of the need for major surgery during study treatment
♦ Proteinuria as demonstrated by urine dipstick ≥ 2+ or > 1.0 g of protein in a 24-hour urine collection (All patients with ≥ 2+ protein on dipstick urinalysis at baseline must undergo a 24-hour urine collection for protein and will become eligible if ≤ 1.0 g of protein detected) within 2 weeks of randomization.
♦ History of inflammatory bowel disease or any autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, type I diabetes mellitus, vasculitis, or glomerulonephritis ♦ Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this study.
♦ Patients with controlled Type I diabetes mellitus on a stable insulin regimen are eligible
♦ History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
♦ History of radiation pneumonitis/fibrosis in the radiation field is permitted.
♦ Infections:
♦ Signs or symptoms of infection or therapeutic use of antibiotics (except prophylactic antibiotics) within 2 weeks prior to randomization and no severe infections within 4 weeks prior to randomization, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia...
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is progression-free survival rate at 6 months (PFS-6) according to RECIST v1.1 as assessed by the local investigator. Safety is assessed according to CTCAE v4.0. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
♦secondary endpoints are: overall survival, progression free survival, second progression free survival, clinical response, disease control and duration of response as measured by RECIST. Progression-free survival at 6 months, progression free survival, second progression-free survival and clinical response will also be assessed using irRECIST.
♦Tolerability will be summarized by the frequency of treatment regimen modification and reasons for stopping the treatment.
♦Tumor infiltrating lymphocytes (TIL) at enrolment will be analysed on tumor biopsies retrospectively in batch.
Further assessment of the tumor-associated immune microenvironment will measure: the expression of HLA class I, HLA class II, TAP and b2-microglobulin, the expression of PD-L1, at the mRNA (ISH) and protein (IHC) level, the expression of known tumor-associated antigens (TAA) and correlation with the TAA-specific T cell responses in the peripheral blood, the expression of PD-1 on different T cell subpopulations e.g. CD3, CD4, CD8, CD45RO and the expression of PD-L1 on immune cells, the co-expression of CD4, CD25, FOXP3 for identification of Tregs, combined with Ki67 (positive cells represent recently activated Tregs) and CD45RA (negative cells represent non-naïve, TCR-triggered Tregs), expression in T lymphocytes of TCR-signaling proteins e.g. Phospho-ZAP70, phospho-LAT, NFAT; expression of CD1c, CD11c, CD141, CD123, markers that define different dendritic cell subsets; CD68/CD163 (M1, M2 macrophages), CD20 (B lymphocytes), CD117 (mast cells), NKp46 (NK cells) and angiogenesis markers e.g. CD31, CD105, FasL, endothelin B receptor, ICAM1, VCAM1.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Survival and safety is assessed continuously until study end; progression is assessed every 3 cycles during treatment, 9 weekly during years 1-2 and 6 until year 5. The assessment of the tumor-associated immune microenvironment will be performed in formalin-fixed, paraffin-embedded tumor samples and blood samples at baseline, pre-cycle 3 and at time of progression (if feasible). |
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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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Partially blinded for ASA administration (patient and local staff blinded) |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Denmark |
| France |
| Italy |
| Netherlands |
| Spain |
| Switzerland |
| United Kingdom |
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| 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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1. Ninety days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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