Phase III Randomized Trial of Platinum-Based Chemotherapy with Paclitaxel, Bevacizumab, and Atezolizumab in Metastatic, Persistent, or Recurrent Cervical Carcinoma
- Trial ID
- 2024-514179-17-00
- Protocol
- BEATcc
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this randomized Phase III trial is to evaluate the **progression-free survival (PFS)** in patients with metastatic (stage IVB), persistent, or recurrent carcinoma of the cervix. The study aims to determine whether the addition of **atezolizumab** to chemotherapy (cisplatin or carboplatin/paclitaxel) and **bevacizumab** improves PFS compared to chemotherapy and bevacizumab alone. Additionally, the trial seeks to assess if the inclusion of atezolizumab enhances overall survival (OS) in this patient population. These objectives are clinically relevant as they address the potential for improved treatment outcomes in a challenging cancer type, offering insights into the efficacy of combining immunotherapy with standard chemotherapy regimens.
Secondary objectives include: - **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)** - **Pharmacokinetics (PK) of atezolizumab** and the incidence of anti-therapeutic antibodies (ATAs) to evaluate the immune response to atezolizumab.
Participants
The clinical trial involves a total of **71 participants** diagnosed with **metastatic (stage IVB), persistent, or recurrent carcinoma of the cervix**. The study population is exclusively female, with an age range of 18 years and older. Participants were selected based on specific inclusion criteria, including adequate organ function, negative test results for hepatitis, and a life expectancy of at least three months. The trial excludes individuals with prior systemic anti-cancer therapy for metastatic or recurrent disease. Participants are required to have a histologically- or cytologically-confirmed diagnosis of cervical cancer, with certain histologies capped at 20% of the study population. The trial does not include a vulnerable population, and participants must have a GOG/Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Lifestyle considerations such as diet and physical activity are not specified in the trial data provided.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, and controlled study designed to evaluate the efficacy of adding **atezolizumab** to a chemotherapy regimen consisting of platinum chemotherapy plus paclitaxel and **bevacizumab** in patients with metastatic (stage IVB), persistent, or recurrent carcinoma of the cervix. The primary objectives are to assess progression-free survival (PFS) and overall survival (OS) when atezolizumab is included in the treatment regimen. The trial is expected to run until March 31, 2025, with recruitment having commenced on September 25, 2018.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, organ function, and previous treatment history. Following randomization, participants will receive treatment over a maximum period of 42 days, with regular follow-up visits to monitor response to treatment and any adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination from the study.
The expected length of participant involvement is approximately 42 days, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent. The study will also evaluate secondary endpoints such as objective response rate (ORR), duration of response (DOR), and the frequency and severity of adverse events. Participants will be monitored for changes in patient function and quality of life, as well as serum concentrations of atezolizumab. The trial will also explore the relationship between tumor biomarkers and treatment response.
Treatment
The clinical trial involves the administration of **Tecentriq**, a concentrate for solution for infusion, containing the active substance **atezolizumab**. Atezolizumab is a monoclonal antibody classified under the ATC code L01FF05. The pharmaceutical form is a solution for infusion, and it is administered intravenously. The maximum daily dose is 1200 mg, with a total dose not exceeding 1200 mg over a treatment period of 42 days. The administration schedule is designed to ensure optimal therapeutic levels, and participant compliance is monitored throughout the trial. The product is manufactured by Roche Registration GmbH and is authorized for use in the European Union.
Another treatment used in the trial is **Avastin**, a concentrate for solution for infusion, with the active substance **bevacizumab**. Bevacizumab is also a monoclonal antibody, categorized under the ATC code L01FG01. The pharmaceutical form is a solution for infusion, administered intravenously. The dosing regimen involves a maximum daily dose of 15 mg/kg, with a total dose not exceeding 15 mg/kg over a 42-day treatment period. The administration of Avastin is carefully monitored to ensure adherence to the dosing schedule. This product is also manufactured by Roche Registration GmbH and is authorized for use in Iceland.
In addition to the experimental medications, the trial includes standard-of-care chemotherapy, which consists of platinum-based chemotherapy agents such as cisplatin or carboplatin, combined with paclitaxel. These agents are administered according to established protocols for the treatment of metastatic, persistent, or recurrent carcinoma of the cervix. The trial aims to evaluate the efficacy of adding atezolizumab to the chemotherapy regimen with bevacizumab, compared to the chemotherapy regimen with bevacizumab alone, in terms of progression-free survival and overall survival.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression Free Survival (PFS)** and **Overall Survival (OS)**. These endpoints will be used to evaluate the effectiveness of adding atezolizumab to chemotherapy (cisplatin or carboplatin/paclitaxel) and bevacizumab compared to chemotherapy and bevacizumab alone in patients with metastatic, persistent, or recurrent carcinoma of the cervix.
Secondary endpoints will provide additional insights into the treatment's efficacy and include the Objective Response Rate (ORR), Duration of Response (DOR), and the frequency and severity of adverse events. Other secondary measures include the Time from Randomization to First Subsequent Therapy or Death (TFST), Time from Randomization to Second Progression (PFS2), and changes in patient function and quality of life as measured by the EQ-5D-5L questionnaire. The study will also assess serum concentrations of atezolizumab and the prevalence and incidence of anti-drug antibodies (ATAs) to atezolizumab.
These efficacy parameters will be collected and analyzed at various timepoints throughout the trial, with specific methods such as radiologic assessments and patient-reported outcomes being employed to ensure comprehensive evaluation. The trial is designed to provide robust data on the potential benefits of the treatment regimen in improving survival and quality of life for patients with advanced cervical cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Female patients must be ≥18 years of age
- Signed informed consent before any study-specific procedure
- Able (in the investigator´s judgment) to comply with the study protocol
- GOG/Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Life expectancy ≥3 months
- 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
- 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.
- 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.
- 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
- 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
- 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
- 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
- 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.
- Negative Test Results for Hepatitis
- Toxicities related to previous treatments must be recovered to < grade 2 (with the exception of alopecia).
- Female participants must be postmenopausal (≥ 12 months of nontherapyinduced 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.
Exclusion Criteria
- Disease that is suitable for local therapy administered with curative intent
- Prior radiotherapy delivered using cobalt.
- Patients with Stage IVA not amendable to concurrent chemo-radiation as primary treatment.
- Ongoing disease involving the bladder or rectum at screening/baseline
- Evidence of abdominal free air.
- Bilateral hydronephrosis.
- Patients previously treated with chemotherapy
- Prior treatment with any anti-VEGF drug
- Patients with a concomitant malignancy other than non-melanoma skin cancer
- Known brain metastases or spinal cord compression
- History or evidence, following a neurological examination unless properly treated with standard medical treatment.
- Patients with serious non-healing wound, ulcer, or bone fracture.
- Acute intestinal obstruction or sub-occlusion episode in the last 6 months.
- Active GI bleeding or GI ulcer
- History of Crohn's disease or inflammatory bowel disease
- Prior bowel resection ≤6 weeks preceding first study dose
- History of diverticulitis requiring medical intervention.
- NCI CTCAE (version 5.0) grade ≥2 enteritis.
- Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to D1C1.
- Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to D1C1.
- Patients with active bleeding or pathologic conditions that carry high risk of bleeding
- 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.
- Patients with pre-existing Grade 2 or greater peripheral neuropathy.
- History of any grade ≥3 venous thromboembolic event (VTE).
- Patients with clinically significant cardiovascular disease.
- Left ventricular ejection fraction defined by MUGA/ECHO below the institutional lower limit of normal
- Uncontrolled tumor-related pain.
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
- Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.
- History of autoimmune disease.
- 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.
- Active tuberculosis
- 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.
- Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
- Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1,Day 1.
- Known human immunodeficiency virus (HIV).
- 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.
- 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.
- Treatment with systemic immunostimulatory agents within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1.
- Treatment with systemic immunosuppressive medications within 2 weeks prior to Cycle 1, Day 1. The use of corticosteroids is allowed as premedication for paclitaxelbased regimen
- 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.
- 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.
- Women that are breastfeeding or pregnant
- Known hypersensitivity to bevacizumab, atezolizumab or any of theirs excipients (including Cremophor).
- No medical or psychiatric illness that may impede the performance of a systemic or surgical treatment
- Demonstration of any other neurological or metabolic dysfunction
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 25 Sept 2018 | 128 |
 Germany | Not Recruiting | 25 Sept 2018 | 21 |
 Italy | Not Recruiting | 25 Sept 2018 | 41 |
 Norway | Not Recruiting | 25 Sept 2018 | 11 |
 Spain | Not Recruiting | 25 Sept 2018 | 127 |
 Sweden | Not Recruiting | 25 Sept 2018 | 11 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Tecentriq 1 200 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 1200 | 42 | PRD5434939 |
Avastin 25 mg/ml concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 15 | 42 | PRD2153902 |