Phase II Randomized Trial of Atezolizumab with Chemoradiotherapy in Locally Advanced Cervical Cancer

Trial ID: 2024-515533-15-00
Protocol: CSET N°2017/2608
Sponsor: Institut Gustave Roussy

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Diseases & Conditions

Cervix carcinoma

Objectives

The primary objective of this randomized phase II trial is to assess the clinical benefits of adding **atezolizumab** to standard chemoradiotherapy (CRT) in patients with locally advanced cervical cancer. This evaluation focuses on progression-free survival (PFS) as determined by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). The clinical relevance of this objective lies in determining whether the addition of atezolizumab can enhance treatment outcomes compared to CRT alone, potentially leading to improved management strategies for this patient population.

Secondary objectives include:

Evaluating the efficacy of atezolizumab plus standard CRT compared with CRT alone, as measured by objective response rates, locoregional control, and overall survival (OS).
Assessing the safety of atezolizumab in combination with CRT compared to CRT alone, focusing on the incidence and severity of acute and delayed radiation-induced side effects.
Conducting translational research to assess blood- and tissue-based biomarkers predictive of response to atezolizumab and associated with outcomes independent of treatment, as well as changes in these biomarkers during treatment.
Determining biological changes during treatment through MRI sequence analysis to tailor the prescribed dose and improve therapy efficacy for future patients.

Participants

The clinical trial focuses on evaluating the effects of adding atezolizumab to standard chemoradiotherapy in patients with **locally advanced cervical cancer**. The study population comprises exclusively female participants, aged 18 years and older, with no upper age limit specified. Participants are required to have a histologically confirmed diagnosis of cervical cancer, including squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must demonstrate adequate hematologic and end-organ function, as defined by specific laboratory criteria. The trial population is selected based on their ability to comply with the study protocol and their geographical, social, and psychological capacity to undergo the required follow-up. Lifestyle considerations include the requirement for women of childbearing potential to use effective contraception or remain abstinent during the treatment period and for a specified duration afterward. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is a **randomized**, **phase II** study designed to evaluate the efficacy of **atezolizumab** in combination with standard chemoradiotherapy (CRT) compared to CRT alone in patients with **locally advanced cervical cancer**. The trial employs a **double-blind** and **controlled** methodology to ensure unbiased results. The primary objective is to assess progression-free survival (PFS) as per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). The trial is expected to conclude by May 2025, with recruitment having commenced in August 2018.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of cervical cancer, and adequate organ function. Following randomization, participants will receive treatment and attend regular follow-up visits to monitor disease progression, treatment response, and any adverse events. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination from the study.

The expected duration of participant involvement is approximately one year, contingent upon individual response to treatment and absence of disease progression. Conditions that may lead to early termination include significant adverse reactions, withdrawal of consent, or investigator decision based on clinical judgment. The trial's primary endpoint is progression-free survival, with secondary endpoints including overall survival, complete response rate, locoregional control, distant tumor control, and toxicity assessment. These endpoints will be evaluated using standardized criteria to ensure consistency and reliability of the data collected throughout the study.

Treatment

The clinical trial involves the administration of **atezolizumab**, marketed under the name Tecentriq, which is a **humanized immunoglobulin (IgG1) monoclonal antibody**. Atezolizumab is provided as a concentrate for solution for infusion, specifically formulated as a 1,200 mg dose. The pharmaceutical form is a solution for infusion, and the route of administration is via **intravenous (IV) infusion**. The dosing schedule for atezolizumab involves a maximum daily dose of 1,200 mg, with a total maximum dose of 24,000 mg over the course of the treatment period. The treatment period is defined as one cycle, with the frequency of administration determined by the study protocol. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen.

In addition to the experimental treatment with atezolizumab, participants in the trial receive standard chemoradiotherapy (CRT) as part of the study design. The trial is structured to compare the effects of atezolizumab in combination with CRT against CRT alone. The standard-of-care therapy, CRT, serves as the comparator treatment in this randomized phase II trial. The primary objective is to assess the clinical benefits of adding atezolizumab to CRT, focusing on progression-free survival as evaluated by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). The trial does not utilize a placebo, as the comparator is the established standard treatment for locally advanced cervical cancer.

Efficacy

Efficacy in this clinical trial will be assessed primarily through **progression-free survival (PFS)**, which is defined as the time from randomization to the first documented occurrence of disease progression or death from any cause, as determined by the investigator using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Data for patients without disease progression or death will be censored at the date of the last follow-up.

Secondary endpoints include overall survival (OS), complete response rate at 8 weeks, locoregional control, distant tumor control, and toxicity. Overall survival is defined as the time from randomization to death due to any cause. The complete response rate at 8 weeks is defined as the percentage of patients with measurable disease at baseline who achieve a complete response after treatment initiation, as determined by RECIST v1.1 criteria. Locoregional control is defined as the cumulative rate of locoregional recurrence or progression, with censoring of deaths without locoregional recurrence or progression. Distant tumor control is defined as the cumulative rate of metastatic events, with censoring of deaths without metastatic progression. Toxicity is defined as any adverse drug reaction occurring within 6 months following brachytherapy (acute toxicity) or more than 6 months following brachytherapy (late toxicity), graded using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTC-AE v4.03) at each visit.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Signed informed consent (after informing the patient).
Age ≥18 years old. Patients above 70 years old will be screened according to the G-8 screening tool. If required (G-8 score ≤14), a consultation with an onco-geriatrician will be held in order to confirm the patient eligibility.
Histologically confirmed cancer of the uterine cervix: squamous cell carcinoma (SCC), adenocarcinoma, or adenosquamous carcinoma
At least one evaluable lesion according to RECIST v1.1 criteria for the assessment of the principal judgment criteria. At baseline, lesion(s) must be ≥10 mm in the longest diameter (except lymp nodes which must have a short axis ≥15 mm).
International Federation of Gynecology and Obstetrics (FIGO 2009) classification (confirmed by clinical staging and/or imaging): (i) stage IB1-IIA tumour with positive pelvic nodal status, as assessed by magnetic resonance imaging (MRI) and/or fluorine-18 fluorodeoxyglucose positron emission tomography (18-FDG PET)/computerised tomography (CT); (ii) stage IIB-IVA tumour, regardless of pelvic lymph node involvement; (iii) stage IVB tumours only if the metastases are limited to the para-aortic lymph nodes. No evidence of metastatic disease outside the para-aortic area by primary staging (including clinical examination, pelvic MRI, 18-FDG PET, +/- laparoscopic para-aortic lymph node staging).
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
Adequate haematologic and end-organ function, defined by the following laboratory results obtained within 15 calendar days prior to the first study treatment: a. Absolute neutrophil count (ANC) ≥1,500/mm3 (≥1.5 x 109/L) without granulocyte colony-stimulating factor (G-CSF) support. b. Total white blood cells (WBC) >2,000/mm3 (>2.0 x 109/L) (including Polymorphonuclear neutrophils > 1,500/mm3 or 1.5 x 109/L) c. Lymphocyte count ≥500/mm3 (≥ 0.5 x 109/L) d. Platelet count ≥ 100,000/mm3 (≥ 100 x 109/L) without transfusion. e. Haemoglobin ≥ 9.0 g/dL (90 g/L; patients may be transfused to meet this criterion). f. International Normalized Ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × upper limit of normal (ULN) for patients not receiving therapeutic anticoagulation. Patients receiving therapeutic anticoagulation should be on a stable dose. g. Creatinine <1.5 ULN or calculated creatinine clearance (CrCL) ≥ 45 mL/min (calculated using the Cockcroft-Gault formula). h. Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase <2.5 x ULN. i. Serum bilirubin <1.5 x ULN.
Proteinuria < 200 mg/dL (2 g/L). Patients with ureteral stent or with bladder invasion are eligible if the proteinuria is above the former threshold.
Ability to comply with the study protocol.
Geographical, social and psychological ability to undergo the follow-up required by the study.
Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhoea) and not surgically sterile: a. Must agree to either use an acceptable contraceptive method* or to remain abstinent** (refrain from heterosexual intercourse) during the treatment period and for at least 5 months after the last dose of atezolizumab in arm B and at least 6 months after the last cisplatin/carboplatin dose in arm A. * Acceptable contraceptive methods include single or combined contraceptive methods that result in a failure rate of < 1% per year, such as: tubal ligation, male sterilization, 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. ** 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. b. Must have a negative serum pregnancy test result within 7 days prior to initiation of study drug.
Patients must be affiliated to a social security system or beneficiary of the same, as per local regulatory requirements

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Exclusion Criteria

Histological types of cervical cancer other than those listed in the inclusion criteria (based on FIGO 2009 classification), including: a. Stage IB1, IB2 and IIA cervical cancer with no regional lymph node metastases (N0). b. Stage IVB cervical cancer with presence of distant metastases other than para-aortic lymph node metastases.
Treatment with another investigational therapy within 30 days prior to initiation of the study drug.
Major surgical procedure within 4 weeks prior to randomisation or anticipation of the need for a major surgical procedure during the study other than for diagnosis. The following are not considered a major surgical procedure and are therefore permitted: (i) placement of central venous access catheter(s) (e.g., port or similar); (ii) surgical lymph node staging with no perioperative complications; (iii) placement of ureteral catheters.
History of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins.
Known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component of the atezolizumab formulation.
Any contraindication to the use of cisplatin and/or carboplatin
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, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, meningoencephalitis, or glomerulonephritis (see Appendix 6 for a more comprehensive list of autoimmune diseases) with the following exceptions: patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone, patients with controlled Type 1 diabetes mellitus on a stable insulin regimen, and patients with mild autoimmune skin disorders (such as eczema or atopic dermatitis involving <10% of the skin) may be eligible for this study.
History of idiopathic pulmonary fibrosis (IPF, including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or active pneumonitis.
Peripheral neuropathy ≥grade 2.
Positive test for human immunodeficiency virus (HIV).
Active hepatitis B (positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C (positive hepatitis C virus antibody [HCVAb] test at screening). Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive hepatitis B core antibody [HBcAb] test) are eligible.
Prior surgery for cervical cancer unless cone resection and paraaortic lymphadenectomy.
Known active tuberculosis.
Receipt of a live, attenuated vaccine within 4 weeks prior to randomisation or anticipation that such a live, attenuated vaccine will be required during the study. Note: Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist®) within 28 days prior to randomisation, during treatment or within 5 months following the last dose of atezolizumab.
Prior treatment with CD137 agonists, anti-PD-1, or anti-PD-L1 therapeutic antibody or immune checkpoint targeting agents.
Prior pelvic radiotherapy, other radiotherapy, chemotherapy or immunotherapy.
Any malignancy other than the disease under study in the past 5 years excepting skin cancers such as BCC or SCC.
Pregnant or lactating women, or intending to become pregnant during the study.
For patient ≥ 70 years old with a G-8 score ≤ 14, unconfirmation of patient eligibility done by the onco-geriatrian at screening
History of clinically relevant cardiovascular disease, congestive heart failure (New York Heart Association [NYHA] Class II or greater; see Appendix 3), or a known left ventricular ejection fraction (LVEF) <50%, symptomatic coronary artery disease, poorly controlled cardiac arrhythmia, or myocardial infarction.
Active inflammatory bowel disease, lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome.
Serious infection requiring oral or IV antibiotics within 4 weeks prior to randomisation, including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia.
Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to randomisation. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed.
Treatment with systemic immunostimulatory agents (such as interferons or IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to randomisation.
Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator’s judgment.
Any other serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in and completion of the study.
Patients under judicial protection (curatorship, tutorship) and/or deprived of freedom.