| Protocol No: | ECCT/22/01/04 | Date of Protocol: | 27-08-2021 |
| Study Title: | 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 |
| Study Objectives: | The primary efficacy objectives, secondary efficacy objectives, exploratory efficacy objectives, safety objectives, pharmacokinetic objective, immunogenicity objective, exploratory immunogenicity objective, exploratory biomarker objective, exploratory health status utility objective and their corresponding endpoints have been listed in Table 1 of the Protocol YO42137, Version 5 attached.
The primary and secondary objectives have been listed below. Primary Objectives
Secondary Objectives
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| Laymans Summary: |
The purpose of this study is to compare the effects, good or bad, of atezolizumab plus tiragolumab versus atezolizumab plus placebo or double placebo on patients with esophageal cancer who have received chemoradiotherapy considered standard in this setting without progression of their disease. A placebo looks like a drug but has no active ingredient.
About 750 people will take part in this study globally.
Atezolizumab and tiragolumab are experimental drugs, which means health authorities have not approved these drugs, alone or in combination, for the treatment of esophageal cancer.
Atezolizumab is an antibody (a protein similar to the ones produced by your body's immune system) that blocks the programmed death-ligand 1 (PD-L1) pathway. The PDL1 pathway is involved in regulating the body's natural immune response, but tumors can take advantage of this regulation to partially resist or evade the immune system. By blocking the PDL1 pathway, atezolizumab may help your immune system stop or reverse the growth of tumors. Atezolizumab is approved in some countries for the treatment of advanced bladder cancer, lung cancer, breast cancer, liver cancer, and skin cancer.
Tiragolumab is an antibody that blocks the TIGIT pathway. The TIGIT pathway is involved in regulating the body's natural immune response, but tumors can take advantage of this regulation to partially resist or evade the immune system. By blocking the TIGIT pathway, tiragolumab may help your immune system stop or reverse the growth of tumors.
This study will evaluate the efficacy and safety of tiragolumab plus atezolizumab compared with placebo in patients with unresectable esophageal squamous cell carcinoma (or those who are unable or unwilling to undergo surgery) and whose cancers have not progressed following definitive concurrent chemoradiotherapy (dCRT).
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| Abstract of Study: |
A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBOCONTROLLED 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
PROTOCOL NUMBER: YO42137
TEST PRODUCTS: Tiragolumab (RO7092284), Atezolizumab (RO5541267)
PHASE: Phase III
RATIONALE
Esophageal cancer is the seventh most commonly diagnosed cancer worldwide and the sixth most common cause of cancer-related death (572,000 new cases; 509,000 deaths in 2018); the latter signifying that esophageal cancer will be responsible for an estimated 1 in every 20 cancer deaths in 2018 (Bray et al. 2018).
Approximately 70% of cases occur in men, and there is a 2- to 3-fold difference in incidence and mortality rates between the sexes worldwide (Bray et al. 2018). Most esophageal cancers can be categorized into two histological subtypes: squamous cell carcinoma and adenocarcinoma, with differences in prevalence depending on the region. Squamous cell carcinoma is the most common esophageal cancer in Asia and Africa, while adenocarcinoma is increasing in frequency in North America and Western Europe (Lin et al. 2013; Noone et al. 2017; Bray et al. 2018). Another major difference is the disease etiology: tobacco and alcohol abuse are the major risk factors for squamous cell carcinoma, whereas gastroesophageal reflux disease and Barrett’s esophagus are the two major risk factors for adenocarcinoma (Engel et al. 2003). Although the incidence of esophageal adenocarcinoma and esophagogastric junctional carcinoma has increased in the United States and Western Europe, esophageal squamous cell carcinoma accounts for ~78% of all esophageal cases worldwide, and for ~90% of patients in the
highest-risk regions of Northern Iran through Central Asia to North-Central China (Arnold et al. 2015; Edgren et al. 2013; Lagergren et al 2017).
Most esophageal cancer patients are diagnosed with advanced disease, where the disease is frequently recurrent and treatment options can include surgery,
chemotherapy, and/or radiotherapy. Treatments can extend survival but are largely palliative; and median survival time is less than 1 year (Zhang 2013; Smyth et al. 2017).
The prognosis of esophageal squamous cell carcinoma remains poor, and 5-year survival rates are between 10%-20% across the United States, Europe, and Asia (Weidmann and Mössner 2013; Arnold et al. 2015; Lordick et al. 2016; Wang et al. 2016; Murphy et al. 2017; Cheng et al. 2018; Ilson and van Hillegersberg 2018; NCCN 2019).
The impact of esophageal cancer on patients is multi-faceted. Most affected individuals present with physical symptoms, primarily dysphagia, which can result in unintentional weight loss and loss of appetite (Daly et al. 2000). However, patients with esophageal cancer also frequently report poor emotional well-being, and in particular high rates of anxiety and depression (Hu et al. 2015). Each of these symptoms has a significant impact on different aspects of patients’ functioning and quality of life. Hence, there remains a significant need for novel therapeutic agents for this patient population.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy and safety of tiragolumab plus atezolizumab compared with placebo in patients with unresectable esophageal squamous cell
carcinoma (or those who are unable or unwilling to undergo surgery) and whose cancers have not progressed following dCRT.
In this protocol, "study treatment" refers to the combination of treatments assigned to patients as part of this study:
The primary efficacy objectives, secondary efficacy objectives, exploratory efficacy objectives, safety objectives, pharmacokinetic objective, immunogenicity objective, exploratory immunogenicity objective, exploratory biomarker objective, exploratory health status utility objective and their corresponding endpoints have been listed in Table 1 of the Protocol YO42137, Version 5 attached.
Study design
This is a Phase III, randomized, double-blind, three-arm, global, multicenter, placebo-controlled study designed to evaluate the safety and efficacy of tiragolumab in combination with atezolizumab compared with placebo in patients with unresectable esophageal squamous cell carcinoma (or those who are unable or unwilling to undergo surgery) and whose cancers have not progressed following dCRT.
This study will enroll approximately 750 patients randomized in a 1:1:1 ratio to one of three treatment arms:
Arm A: tiragolumab atezolizumab
Arm B: tiragolumab placebo atezolizumab
Arm C: tiragolumab placebo atezolizumab placebo
Randomization will be stratified according to the following stratification factors:
This study will initially enroll approximately 750 patients across all sites in a global enrollment phase. After completion of the global enrollment phase, additional patients may be subsequently randomized into the treatment arms in an extended China enrollment phase at sites in China to ensure a total of approximately 190 patients in a China subpopulation. The global population will include all patients enrolled during the global enrollment phase (including patients enrolled in China during that phase), and the China subpopulation will include all patients enrolled in China (i.e., during both the global enrollment phase and the extended China
enrollment phase). The patients enrolled in the China extension phase will undergo the same schedule of activities and will receive study drug as in the global study.
Patients who do not initially meet the eligibility criteria for participation in this study (screen failure) may qualify for one re-screening opportunity (for a total of two screenings per participant) at the investigator's discretion.
Patients will receive either tiragolumab plus atezolizumab (Arm A), placebo plus atezolizumab (Arm B), or double placebo (Arm C).
In Arm A, patients will receive atezolizumab at a fixed dose of 1200 mg administered by IV infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle, followed by tiragolumab at a fixed dose of 600 mg administered by IV infusion Q3W on Day 1 of each 21-day cycle for up to 17
cycles.
In Arm B, patients will receive atezolizumab at a fixed dose of 1200 mg administered by IV infusion Q3W on Day 1 of each 21-day cycle, followed by placebo administered by IV infusion Q3W on Day 1 of each 21-day cycle for up to 17 cycles.
In Arm C, patients will receive placebo administered by IV infusion Q3W on Day 1 of each 21-day cycle in two consecutive administrations for up to 17 cycles.
Treatment should continue until unacceptable toxicity or radiographic progression per investigator-assessed Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), or up to 17 cycles of treatment. Patients will undergo tumor assessments at scheduled intervals during the study. Additional scans will be performed as clinically indicated. Tumor assessments will continue regardless of whether treatment has been delayed, until radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first.
Tumor assessments are to continue according to schedule in patients who discontinue treatment for reasons other than radiographic disease progression per RECIST v1.1, even if they start new anti-cancer therapy, until consent is withdrawn, death or the study is terminated by the Sponsor, whichever occurs first.
For equivocal findings of radiographic progression (e.g., very small and uncertain new lesions; cystic changes or necrosis in existing lesions), study treatment should be continued and a confirmatory scan must be performed again within 46 weeks. If at the next scheduled assessment, progression is confirmed, the date of progression recorded should be the earlier date when progression was suspected.
Following treatment discontinuation, information on survival and subsequent anti-cancer therapies will be collected until death, loss to follow-up, withdrawal of consent, or study termination by the Sponsor, whichever occurs first.
Patients will undergo patient-reported outcome (PRO) assessments at specified time points during treatment and for up to 1 year after treatment discontinuation.
Safety assessment will include the incidence, nature, and severity of adverse events and laboratory abnormalities graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). Severity for CRS will also be graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading scale. Laboratory safety assessments will include the regular monitoring of hematology and blood chemistry.
Serum samples will be collected to monitor tiragolumab and atezolizumab pharmacokinetics and to detect the presence of antibodies to tiragolumab and atezolizumab.
Patient samples, including archival and fresh tumor tissue, serum, plasma, and blood samples, will also be collected for exploratory biomarker assessments.
Inclusion criteria
Patients must meet the following criteria for study entry:
Exclusion criteria
Patients who meet any of the following criteria will be excluded from study entry:
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