| 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 | 20.0 |
| 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 |
| Determine whether the addition of atezolizumab to chemotherapy (cisplatin/paclitaxel [CP]) plus bevacizumab improves overall survival (OS) compared to CP plus bevacizumab. |
|
| E.2.2 | Secondary objectives of the trial |
- Progression free survival (PFS)
- 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. |
|
| 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 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 of 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:
o Negative hepatitis B surface antigen (HBsAg) test at screening
o Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening.The HBV DNA test will be performed only for patients who have a positive total HBcAb test.
o Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening.The HCV RNA test will be performed only for patients who have a positive HCV antibody test.
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.
o Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal or postovulation methods) and withdrawal are not acceptable methods of contraception
o Examples of contraceptive methods with a failure rate of <1% per year include tubal ligation, male sterilisation, hormonal implants, established proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of <1% per year. Barrier methods must always be supplemented with the use of a spermicide. |
|
| 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.
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 4.0) 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. Uncontrolled tumor-related pain.
27. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures. Patients with indwelling catheters are allowed.
28. Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.
29. History of autoimmune disease.
30. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
31. History of radiation pneumonitis in the radiation field (fibrosis) 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 Influenza vaccination should be given during influenza season only.
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.
41. The use of corticosteroids is allowed as premedication for paclitaxel-based regimen. All patients should be premedicated prior to receiving chemotherapy (including with corticosteroids) according to the prescription information of paclitaxel and cisplatin and the institutional standard of care guidance.
42. Currently participating or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of study treatment.
43. 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.
44. Women that are breastfeeding or pregnant.
45. Known hypersensitivity to bevacizumab, atezolizumab or any of theirs excipients (including Cremophor).
46. Demonstration of any other neurological or metabolic dysfunction.
47. 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) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 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) |
- Progression free survival (PFS)
- 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PFS using the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST v1.1).
- 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
- 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 |
|
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 |
| Australia |
| Israel |
| Japan |
| New Zealand |
| United States |
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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