Chemotherapy plus Paclitaxel with Bevacizumab and Atezolizumab versus Chemotherapy plus Paclitaxel and Bevacizumab in Carcinoma of the Cervix

JRCT ID: jRCT2041190037

Registered date:05/06/2019

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Metastatic (stage IVB), Persistent, or Recurrent Carcinoma of the Cervix
• Date of first enrollment: 14/08/2019
• Target sample size: 56
• Countries of recruitment: Spain,Japan,Germany,Japan,France,Japan,USA,Japan,Italy,Japan,Norway,Japan,Sweden,Japan
• Study type: Interventional

Intervention(s)

- Arm A (Control arm): cisplatin 50mg/m^2 or carboplatin AUC 5+paclitaxel 175mg/m^2+bevacizumab 15mg/kg i.v D1 Q3W. Patients who achieve a complete response after 6 and more treatment cycles may be allowed to continue only on biologic therapy, namely bevacizumab, upon investigator discussion.
- Arm B (Experimental arm): cisplatin 50mg/m^2 or carboplatin AUC 5+paclitaxel 175mg/m^2+bevacizumab 15mg/kg+atezolizumab 1200mg i.v, D1 Q3W. Patients who achieve a complete response after 6 and more treatment cycles may be allowed to continue only on biologics therapy, namely bevacizumab plus atezolizumab, upon investigator discussion.

Outcome(s)

Primary Outcome

- Progression free survival (PFS) based on investigator assessment using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
- Progression Free Survival (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. Patients who had not experienced an event at the data cut-off date or patients who are withdrawn from the study without documented progression will be censored at the date of the last tumor assessment when the patient was known to be progression free. Patients without a known post baseline tumor assessments but known to be alive will be censored at the time of randomization date.
- Overall Survival (OS), defined as the observed length of life from entry into the study (day of randomization) to death or the date of last contact.

Secondary Outcome

- Objective Response Rate (ORR) as assessed by RECIST v1.1
- Duration of response (DOR) by RECIST v1.1
- Frequency and severity of adverse events as assessed by CTCAE version 5.0 for the regimens administered on this study.
- 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, by assessment timepoint and between treatment arms, as assessed by the functional and GHS/HRQoL scales of EORTC QLQ-C30.
- Serum concentration (Cmin and Cmax) of atezolizumab at specified timepoints. Incidence of ATAs during the study relative to the prevalence of ATAs at baseline.
- Prevalence of ATAs to atezolizumab at baseline and incidence of ATAs to atezolizumab during the study.

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Female

Include criteria

1. Female patients must be 18 and more 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 and more 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 and more 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:
- Hemoglobin 9 and more g/dL (transfusion permitted)
- ANC 1.5x10^9/L and more
- Lymphocyte count 0.5x10^9/L and more
- Platelet count 100x10^9/L and more
11. Adequate liver function:
- Serum albumin 2.5 g/dL and more
- Total serum bilirubin 1.5xULN and less
- AST and ALT 2.5xULN and less or 5xULN and more if tumor involvement (liver) is present
12. Adequate renal function:
- Patients with serum creatinine less than 1.5xULN
- Urine dipstick for proteinuria less than 2+. Patients discovered to have 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate 1 and more g of protein in 24 hours or urine protein/creatinine (UPC) ratio of 1.0
13. Adequate coagulation:
- 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 PTT less than 1.5xULN
14. Negative Test Results for Hepatitis
15. Toxicities related to previous treatments must be recovered to less than grade 2 (with the exception of alopecia).
16. Female participants must be postmenopausal (12 and more 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 less than 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.

Exclude criteria

1.Disease that is suitable for local therapy administered with curative intent
2.Prior radiotherapy delivered using cobalt (rather than a linear accelerator)
3.Patients with Stage IVA not amenable to concurrent chemo-radiation as primary treatment will not be eligible.
4.Ongoing disease involving the bladder or rectum at screening/baseline:
- In patients with pelvic disease, absence of tumor in the bladder or rectal mucosa must be demonstrated by MRI (preferred method, or endoscopy/cystoscopy if MRI is not easily accessible) within 28 days before enrolment
5.Evidence of abdominal free air
6.Bilateral hydronephrosis, unless it can be alleviated by ureteral stent(s) or percutaneous drainage
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, including bevacizumab, CD137 agonists or immune checkpoint blockade therapies, anti-PD1, or anti-PDL1 therapeutic antibodies or anti-CTLA 4.
9.Patients with a concomitant malignancy other than non-melanoma skin cancer. Patients with a prior invasive malignancy (except non-melanoma skin cancer) who have had any evidence of disease within the last 5 years or whose prior malignancy treatment contraindicates the current protocol therapy.
10.Known brain metastases or spinal cord compression. It is mandatory to perform a scan of the brain in cases of suspected brain metastases (CT or MRI) or spinal cord compression (MRI).
11.History or evidence, following a neurological examination, of central nervous system disorders, unless properly treated with standard medical treatment. History of cerebrovascular accident, transient ischemic attack or subarachnoid hemorrhage within six months of the first date of treatment on this study.
12.Patients with serious non-healing wound, ulcer, or bone fracture. This includes history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess for which an interval of 6 months must pass before study entry. In addition, the patient must have undergone correction (or spontaneous healing) of the perforation/fistula and/or the underlying process causing the fistula/perforation.
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 and more weeks preceding the first study dose
17.History of diverticulitis requiring medical intervention
18.NCI CTCAE (ver 5.0) G2 or less enteritis
19.Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1, Cycle 1 (C1D1).
20.Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to C1D1.
21.Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
22.Current or recent (within 10 days before the first dose of study drug) chronic daily treatment with aspirin (above 325 mg/day), clopidogrel (above 75 mg/day), or current or recent (within 10 days before first dose of bevacizumab) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes.
23.Patients with pre-existing G2 or greater peripheral neuropathy
24.History of any G3 and more venous thromboembolic event
25.Patients with clinically significant cardiovascular disease. This includes:
- Uncontrolled hypertension, defined as systolic 150 and more mm Hg or diastolic 90 and more mm Hg maintained over time and despite antihypertensive treatment
- Myocardial infarction or unstable angina within 6 months before first dose of study drug
- New York Heart Association Grade II or greater congestive heart failure
- Serious cardiac arrhythmia requiring medication. This does not include asymptomatic, atrial fibrillation with controlled ventricular rate.
- Peripheral vascular disease G3 and more (i.e. symptomatic and interfering with activities or daily living needing repair or review)
- History of CVA within 6 months.
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 (once monthly or more frequently). Patients with indwelling catheters are allowed.
29.Uncontrolled hypercalcemia (above 1.5 mmol/L ionized calcium or calcium above 12 mg/dL or corrected serum calcium above ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.
30.History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, glomerulonephritis or celiac 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 (fibrosis) is permitted.
32.Active tuberculosis
33.Severe infections within 4 weeks prior to C1D1, 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 C1D1
35.Received therapeutic oral or IV antibiotics within 2 weeks prior to C1D1
36.Known human immunodeficiency virus
37.Administration of a live, attenuated vaccine within 4 weeks before C1D1 or anticipation that such a live attenuated vaccine will be required during the study Influenza vaccination should be given during influenza season only. Patients must not receive live, attenuated influenza vaccine within 4 weeks prior to C1D1 or at any time 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 (including but not limited to IFNs, IL-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to C1D1
40.Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to C1D1
41.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.
42.Prior anti-cancer monoclonal antibody, 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 their excipients (including Cremophor)
45.Demonstration of any other neurological or metabolic dysfunction, found upon physical examination or laboratory tests involving a reasonable suspicion of the existence of a disease or condition that contraindicates the use of an experimental drug, or that involves an increased risk to the patient of treatment-related complications
46.No medical or psychiatric illness that may impede the performance of a systemic or surgical treatment

Related Information

• Primary Sponsor: Takekuma Munetaka
• Source(s) of Monetary Support: Chugai Pharmaceutical Co., Ltd.
• Secondary ID(s): NCT03556839