| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic (stage IVB), Persistent, or Recurrent Carcinoma of the Cervix |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008342 |
| E.1.2 | Term | Cervix carcinoma |
| 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 |
-to determine the progression free survival (PFS) of combining atezolizumab to chemotherapy (cisplatin/paclitaxel [CP]) and bevacizumab compared to CP and bevacizumab
-to determine whether the addition of atezolizumab to chemotherapy (CP) plus bevacizumab improves overall survival (OS) compared to CP plus bevacizumab. |
|
| E.2.2 | Secondary objectives of the trial |
- Objective Response Rate (ORR)
- Safety and tolerability
- Duration of response (DOR)
- Time from randomization to first subsequent therapy or death (TFST)
- Time from randomization to second progression (PFS2)
- Patient-reported outcomes (PROs) of function and health related quality of life (HR-QOL)
- PK of atezolizumab and determine the incidence of ATAs |
|
| 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 |
- PROs of disease and/or treatment-related symptoms
- Treatment burden patients.
- Patient’s health utility
- PD-L1 expression in tumor infiltrating lymphocytes (TILs) and cervical cancer cells.
- Relationship between the phenotype of tumor infiltrating lymphocytes (TILs) in archival and/or on-study biopsies and clinical outcomes.
- Correlation between oncogenic HPV and histological subtypes with the expression of tumor and stromal immune biomarkers and with clinical outcomes.
- Biomarkers predictive of response to atezolizumab, prognostic of the disease or associated to the anti-tumor effect of treatmet (pharmacodynamic).
- Effect of antibiotic (ATB) use on the efficacy of atezolizumab.
- To Assess the possible of ATAs
Biomarker Analyses
Genetic characterization of tumor biopsy and blood samples. The main goal is to evaluate whether the biomarkers under consideration have prognostic or predictive value. To explore associations between biomarkers and clinical outcomes
|
|
| E.3 | Principal inclusion criteria |
1. Female patients must be ≥18 years of age.
2. Signed informed consent before any study-specific procedure
3. Able (in the investigator´s judgment) to comply with the study protocol
4. GOG/Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
5. Life expectancy ≥3 months
6. Histologically- or cytologically-confirmed diagnosis of metastatic (stage IVB), persistent, or recurrent cervical cancer (histologies other than squamous cell, adenocarcinoma, or adenosquamous will be excluded) not amenable for curative treatment with surgery and/or radiation therapy. The inclusion of patients with adenocarcinoma histology will be capped to 20% of the whole study population.
7. No prior systemic anti-cancer therapy for metastatic or recurrent disease.
- Concurrent chemo-radiotherapy treatment with curative intent or adjuvant chemo-radiotherapy must have been completed ≥3 months (90 days) prior to enrollment.
- Palliative radiation therapy (e.g., for pain or bleeding) 6 weeks prior enrollment is allowed as long as this does not affect measurable disease and patients are recovered from its symptoms.
8. Measureable disease by RECIST v1.1 criteria: Patients must have at least 1 "target lesion" to be used to assess response on this protocol as defined by RECIST v1.1. If the only target lesion is limited to the radiation field, a biopsy is required to confirm malignancy.
9. A tumor specimen is mandatory at study entry. This may be an archival biopsy or, in its absence, a tumor biopsy obtained within 3 months of randomization from a non-irradiated lesion. Paired recent biopsies at baseline (lesion not previously irradiated; within 3 months of randomization) and at progression disease will not be mandatory, nevertheless they are encouraged as long as these are feasible.
10. Adequate organ function:
o Hemoglobin ≥9 g/dL (transfusion and / or erythropoietin permitted)
o ANC ≥1.5 × 109/L
o Lymphocyte count ≥0.5 × 109/L
o Platelet count ≥100 x 109/L
11. Adequate liver function:
o Serum albumin ≥2.5 g/dL
o Total serum bilirubin ≤1.5 ×ULN
o AST and ALT ≤2.5 × ULN or ≤5 × ULN if tumor involvement (liver) is present
12. Adequate renal function:
o Patients with serum creatinine <1.5 × ULN
o Urine dipstick for proteinuria <2+. Patients discovered to have 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate <1 g of protein in 24 hours or urine protein/creatinine (UPC) ratio ≤ 1.0
13. Adequate coagulation:
o Blood coagulation parameters (PTT, PT/INR): PT such that international normalized ratio (INR) is ≤1.5 (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin for management of venous thrombosis including pulmonary thromboembolus) and a PTT <1.5 ×
ULN.
14. Negative Test Results for Hepatitis
15. Toxicities related to previous treatments must be recovered to < grade 2 (with the exception of alopecia).
16. Female participants must be postmenopausal (≥ 12 months of non-therapyinduced amenorrhoea) or surgically sterile (absence of ovaries and/or uterus, or who received therapeutic radiation to the pelvis) or otherwise have a negative serum pregnancy test within 7 days of the first study treatment and agree to abstain from heterosexual intercourse or use single or combined contraceptive methods that result in a failure rate of <1% per year during the whole treatment period of the study and for at least 5 months (if the last study dose contained atezolizumab) or 6 months (if the last study dose contained bevacizumab) after the last dose of study treatment. |
|
| E.4 | Principal exclusion criteria |
1. Disease that is suitable for local therapy administered with curative intent.
2. Prior radiotherapy delivered using cobalt.
3. Patients with Stage IVA not amendable to concurrent chemo-radiation as primary treatment.
4. Ongoing disease involving the bladder or rectum at screening/baseline.
5. Evidence of abdominal free air.
6. Bilateral hydronephrosis.
7.Patients previously treated with chemotherapy except when used concurrently with radiation therapy. Patients who have received either concurrent paclitaxel with radiation therapy or carboplatin/paclitaxel as neoadjuvant or adjuvant therapy are ineligible for the study.
8. Prior treatment with any anti-VEGF drug.
9. Patients with a concomitant malignancy other than non-melanoma skin cancer.
10. Known brain metastases or spinal cord compression.
11. History or evidence, following a neurological examination unless properly treated with standard medical treatment.
12. Patients with serious non-healing wound, ulcer, or bone fracture.
13. Acute intestinal obstruction or sub-occlusion episode in the last 6 months.
14. Active GI bleeding or GI ulcer.
15. History of Crohn's disease or inflammatory bowel disease.
16. Prior bowel resection ≤6 weeks preceding first study dose.
17. History of diverticulitis requiring medical intervention.
18. NCI CTCAE (version 5.0) grade ≥2 enteritis.
19. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to D1C1.
20. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to D1C1.
21. Patients with active bleeding or pathologic conditions that carry high risk of bleeding.
22. Current or recent chronic daily treatment with aspirin, clopidogrel, or current or recent use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes.
23. Patients with pre-existing Grade 2 or greater peripheral neuropathy.
24. History of any grade ≥3 venous thromboembolic event (VTE).
25. Patients with clinically significant cardiovascular disease.
26. Left ventricular ejection fraction defined by MUGA/ECHO below the institutional lower limit of normal
27. Uncontrolled tumor-related pain.
28. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures.
29. Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.
30. History of autoimmune disease.
31. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field is permitted.
32. Active tuberculosis.
33. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.
34. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1.
35. Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1,Day 1.
36. Known human immunodeficiency virus (HIV).
37. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study.
38. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
39. Treatment with systemic immunostimulatory agents within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1.
40. Treatment with systemic immunosuppressive medications within 2 weeks prior to Cycle 1, Day 1.
The use of corticosteroids is allowed as premedication for paclitaxel-based regimen.
41. Currently participating or has participated in a study of an investigational agent and received study therapy or used an investigational device within weeks prior to the first dose of study treatment.
42. Prior anti-cancer monoclonal antibody (mAb), prior chemotherapy, targeted small molecule therapy as first line treatment for the treatment of metastatic or recurrent cervical cancer.
43. Women that are breastfeeding or pregnant.
44. Known hypersensitivity to bevacizumab, atezolizumab or any of theirs excipients (including Cremophor).
45. Demonstration of any other neurological or metabolic dysfunction.
46. No medical or psychiatric illness that may impede the performance of a systemic or surgical treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
-Progression free survival (PFS)
-Overall Survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
-Time from randomization to disease progression according to Response Evaluation Criteria in Solid Tumors 1.1 (RECISTv1.1).
-The observed length of life from entry into the study (day of randomization) to death or the date of last contact. |
|
| E.5.2 | Secondary end point(s) |
- Objective Response Rate (ORR)
- Duration of response (DOR)
- Frequency and severity of adverse events
- Time from randomization to first subsequent therapy or death (TFST)
- Time from randomization to second progression (PFS2) based on radiologic assessment, start of a new line of therapy, symptomatic deterioration or death.
- Mean and mean changes from baseline score in patient function (role, physical) and GHS/HRQoL.
- Serum concentration (Cmin and Cmax) of atezolizumab.
- Mean and mean changes from baseline score in disease/treatment-related symptoms
- Proportion of patients reporting each response option
- Utility scores of the EQ-5D-5L questionnaire.
- Relationship between tumour immune-related or disease type-related biomarkers.
- Relationship between certain exploratory biomarkers
Prevalence of ATAs to atezolizumab at baseline and incidence of ATAs to atezolizumab during the study. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- ORR by RECIST v1.1
- DOR by RECIST v1.1
- Adverse events as assessed by CTCAE 4.0
- Time from randomization to first subsequent therapy or death
- Time from randomization to second progression
- Assessment by the functional and GHS/HRQoL scales of EORTC QLQ-C30
- Incidence of ATAs during the study relative to the prevalence of ATAs at baseline
-At baseline, at 1,2,4,8 and 16 and at the end of treatment
- Assessment all symptom items/scales of EORTC QLQ-C30 and QLQ-CX24
- Assessment item GP5 from the FACT-G
- Scores of the EQ-5D-5L questionnaire
- Mutational burden, PD-L1, HPV infection, TILs and cluster of differentiation [CD]8 in tumour tissues and clinical outcomes
- Assessment from plasma before and during/after treatment and clinical outcomes
-Relation ATAs/Endpoints |
|
| 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 | No |
| 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 | 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Chemotherapy plus Bevacizumab |
|
| 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 77 |
| 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 |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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