A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Atezolizumab with or without Tiragolumab (Anti-Tigit Antibody) in Patients with Unresectable Esophageal Squamous Cell Carcinoma whose Cancers have not Progressed following Definitive Concurrent Chemoradiotherapy
- Trial ID
- 2022-502052-30-00
- Protocol
- YO42137
- Sponsor
- F. Hoffmann-La Roche AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of **tiragolumab** combined with **atezolizumab** compared to double placebo, based on investigator-assessed progression-free survival (PFS) and overall survival (OS). Additionally, the study aims to assess the efficacy of placebo combined with atezolizumab compared to double placebo, focusing on investigator-assessed OS. This is clinically relevant as it seeks to determine the potential benefits of adding tiragolumab to atezolizumab in patients with unresectable esophageal squamous cell carcinoma, a condition where treatment options are limited and prognosis is often poor.
Secondary objectives include:
- Evaluating the efficacy of placebo plus atezolizumab compared with double placebo based on investigator and independent review facility (IRF) assessed progression-free survival.
- Assessing the efficacy of tiragolumab plus atezolizumab versus placebo plus atezolizumab to demonstrate the contribution of tiragolumab.
- Comparing the efficacy of tiragolumab plus atezolizumab and placebo plus atezolizumab with double placebo, and evaluating the efficacy of tiragolumab plus atezolizumab versus placebo plus atezolizumab to demonstrate the contribution of tiragolumab.
- Evaluating the safety and tolerability of tiragolumab plus atezolizumab and placebo plus atezolizumab compared with double placebo.
- Characterizing the pharmacokinetics of tiragolumab and atezolizumab.
- Evaluating the immune response to tiragolumab and atezolizumab.
Participants
The clinical trial involves a total of **590 participants** diagnosed with **unresectable esophageal squamous cell carcinoma**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific inclusion criteria, such as a histologically or cytologically confirmed diagnosis of squamous cell carcinoma of the esophagus and having undergone definitive concurrent chemoradiotherapy according to regional oncology guidelines. The trial includes individuals with stage II-IVA unresectable locally advanced disease, as well as stage IVB patients with specific lymph node metastases. Participants are required to have representative archival tumor specimens for PD-L1 expression evaluation. The trial population also includes individuals without hepatitis B or C infections, or those with managed hepatitis B virus DNA levels. The selection process ensures a diverse group of participants, including vulnerable populations, to comprehensively evaluate the efficacy of the treatment under investigation.
Plans and Procedures
The clinical trial is a **Phase III, randomized, double-blind, placebo-controlled** study designed to evaluate the efficacy of **atezolizumab** with or without **tiragolumab** in patients with **unresectable esophageal squamous cell carcinoma** whose cancers have not progressed following definitive concurrent chemoradiotherapy. The trial aims to assess progression-free survival and overall survival as primary endpoints, with secondary endpoints including progression-free survival as determined by an independent review facility, overall response rate, duration of response, and incidence of adverse events. The study is expected to run from February 15, 2021, to January 31, 2027, with a maximum treatment period of 51 weeks for participants.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of esophageal squamous cell carcinoma and completion of definitive concurrent chemoradiotherapy. Randomization into the study must occur within 1-84 days after the last dose of radiation therapy. Follow-up visits will be conducted to monitor the participants' health status, assess treatment efficacy, and record any adverse events. The end-of-study visit will conclude the trial for each participant, during which final assessments will be made.
The expected length of participant involvement is up to 51 weeks, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. Participants will receive either the investigational drugs or placebo via **IV infusion**. The trial is not categorized as low intervention, and it is a confirmatory/registrational trial, indicating its significance in the development program for the investigational drugs. The study is conducted under strict adherence to regional oncology guidelines and regulatory requirements to ensure the safety and well-being of all participants.
Treatment
The clinical trial involves the administration of **Tecentriq** (atezolizumab), a **concentrate for solution for infusion**. This experimental medication is provided in a dosage of 1200 mg and is administered via **intravenous infusion**. The maximum daily dose is 1200 mg, with a total maximum dose of 20.4 g over the treatment period. The treatment is scheduled for a maximum period of 51 weeks. Atezolizumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF05. The product is manufactured by Roche Registration GmbH and has undergone secondary packaging and labeling for clinical trial use.
In addition to Tecentriq, the trial also includes the administration of **Tiragolumab**, another experimental medication. Tiragolumab is also a **concentrate for solution for infusion** and is administered via **intravenous infusion**. The dosage for Tiragolumab is set at 600 mg, with a maximum total dose of 10.2 g over the treatment period, which is also capped at 51 weeks. This protein-based therapeutic is produced by F. Hoffmann-La Roche Ltd and is identified by the sponsor product code RO 709-2284/F03-01.
The study employs a double-blind, placebo-controlled design, incorporating two placebo treatments: **Tecentriq Placebo** and **Tiragolumab Placebo**. These placebos are used to maintain the study's blinding and control for potential placebo effects. The pharmaceutical form, active substance, and administration route for these placebos are not applicable, as they are designed to mimic the appearance and administration of the active treatments without containing the active substances.
Efficacy
The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** and **Overall Survival (OS)**, as determined by the investigator, for the comparison of tiragolumab plus atezolizumab with double placebo, and for placebo plus atezolizumab with double placebo. Secondary endpoints will further evaluate PFS and OS across different treatment comparisons, including tiragolumab plus atezolizumab versus placebo plus atezolizumab, and assessments by an independent review facility (IRF).
Additional secondary endpoints include the confirmed Objective Response Rate (ORR) as determined by both the investigator and IRF, the duration of response, and the proportion of patients experiencing clinically meaningful changes in physical functioning, role functioning, global health status/quality of life, and dysphagia. These will be measured using the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire and the Esophageal Cancer Module 18 Questionnaire. The incidence and severity of adverse events will be graded according to NCI CTCAE v5.0, with specific grading for Cytokine Release Syndrome (CRS) according to the ASTCT consensus grading scale.
Pharmacokinetic assessments will include serum concentrations of tiragolumab and atezolizumab at specified timepoints, as well as the prevalence and incidence of anti-drug antibodies (ADAs) to both tiragolumab and atezolizumab. These efficacy parameters will be collected and analyzed at various stages throughout the trial to ensure comprehensive evaluation of the treatment's impact on patients with unresectable esophageal squamous cell carcinoma.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically or cytologically confirmed diagnosis of squamous cell carcinoma of the esophagus
- Definitive concurrent chemoradiotherapy (dCRT) treatment according to regional oncology guidelines (Such as National Comprehensive Cancer Network [NCCN; see Appendix 10 for recommended treatment], European Society for Medical Oncology [ESMO], Chinese Society of Clinical Oncology [CSCO], etc.) for esophageal cancer and with the following criteria: Patients with inoperable cancer must have received at least 2 cycles of platinum-based chemotherapy and radiation therapy consistent with definitive treatment (50-64 Gy) without evidence of radiographic disease progression per RECIST v1.1, as documented by comparison of scans (pre- and post-dCRT) prior to randomization. Patients with cervical esophageal squamous cell carcinoma may receive higher radiation dose (50-66 Gy), as per local oncology guidelines. Randomization into the study must occur within 1-84 days after the last dose of radiation therapy. Use of herbal therapies/traditional Chinese medicines with anti-cancer activity intended to treat the disease under the study must be discontinued prior to randomization.
- Stage II-IVA per American Joint Committee on Cancer/Union for International Cancer Control, 8th edition, unresectable locally advanced disease (medically or surgery is declined) prior to definitive concurrent chemoradiotherapy (dCRT) – Patients are not expected to undergo tumor resection during the course of the study. – Ineligibility for curative surgery must be based on the documented opinion of the qualified medical, surgical or radiation oncologist. – Stage IVB patients diagnosed with cervical or upper thoracic esophageal squamous cell carcinoma with supraclavicular lymph node metastases only and are deemed suitable for definitive concurrent chemoradiation therapy in the opinion of the treating physician, multidisciplinary team or tumor board are eligible
- Representative archival formalin-fixed, paraffin-embedded (FFPE) tumor specimens < 12 months old, collected prior to initiation of dCRT in either paraffin blocks (preferred over slides) or approximately 10-15 slides (15 slides preferred) containing unstained, freshly cut, serial sections (of the 10-15 slides, 5 are for the stratification PD-L1 testing). The number of slides provided may also be governed by local regulations (e.g., Human Genetic Resources Administration of China) Tumor tissue must be submitted for PD-L1 (SP263) expression evaluation prior to randomization. Tumor tissue should be of good quality based on total and viable tumor content and be submitted with an associated pathology report. Patients whose tumor tissue is not evaluable for PD-L1 expression are not eligible. For the purpose of stratification, the PD-L1 score of the patient’s tumor will be the highest PD-L1 TIC score among all samples tested from a single patient prior to stratification, if multiple samples are submitted. Acceptable samples include core needle biopsies for deep tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. FFPE tumor specimens in paraffin blocks are preferred. Fine-needle aspiration, brushing, cell pellet from effusions and lavage samples are not acceptable.
- Patients without hepatitis B virus (HBV) infection or for patients with a positive hepatitis B surface antigen (HBsAg) test and/or a positive total hepatitis B core antibody (HBcAb) test in the absence of a positive hepatitis B surface antibody (HBsAb) test at screening: HBV DNA < 500 IU/mL Patients with detectable HBV DNA should be managed per institutional guidelines. Initiation of anti-HBV therapy should be ≥ 14 days prior to initiation
- 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.
Exclusion Criteria
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, anti-PD-L1 and anti-T-cell immunoreceptor with Ig and ITIM domains (TIGIT) therapeutic antibodies
- Any unresolved toxicity of NCI CTCAE Grade ≥ 2 from the prior chemoradiation therapy Patients with irreversible and manageable hearing loss are eligible.
- Evidence of complete esophageal obstruction not amenable to treatment
- Histology consistent with small cell esophageal carcinoma, esophageal adenocarcinoma, or mixed carcinoma
- High risk for developing esophageal fistula by clinical assessment or imaging, such as prior history or associated symptoms of esophageal fistula, or primary tumor invasion of the great vessels or trachea
- Prior esophagectomy
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 15 Feb 2021 | 13 |
 Belgium | Not Recruiting | 15 Feb 2021 | 4 |
 France | Not Recruiting | 15 Feb 2021 | 45 |
 Germany | Not Recruiting | 15 Feb 2021 | 19 |
 Greece | Not Recruiting | 15 Feb 2021 | 4 |
 Italy | Not Recruiting | 15 Feb 2021 | 13 |
 Poland | Not Recruiting | 15 Feb 2021 | 48 |
 Portugal | Not Recruiting | 15 Feb 2021 | 6 |
 Spain | Not Recruiting | 15 Feb 2021 | 15 |
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 |
|---|---|---|---|---|---|---|
Tiragolumab | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | IV INFUSION | 600 | 51 | PRD7846761 |
Tiragolumab Placebo | Placebo | N/A | — | — | — | N/A |
Tecentriq Placebo | Placebo | N/A | — | — | — | N/A |
Tecentriq 1 200 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | IV INFUSION | 1200 | 51 | PRD5434943 |