Pharmacy and Poisons Board: Applications

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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 To evaluate the efficacy of tira+atezo compared with double placebo To evaluate the efficacy of placebo + atezo compared with double placebo Secondary Objectives To evaluate the efficacy of tira+atezo versus placebo+atezo to demonstrate the contribution of tiragolumab To evaluate the efficacy of tira+atezo and placebo +atezo compared with double placebo
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).
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: Arm A: tiragolumab + atezolizumab Arm B: tiragolumab placebo + atezolizumab Arm C: tiragolumab placebo + atezolizumab placebo 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: Geographic region: Asia (including but not limited to China, Japan, Korea, Taiwan, Thailand) vs. Rest of World (including but not limited to Israel, Turkey, Russia, Europe, North America, South America, Africa, Australia, New Zealand) PD-L1 expression: tumor and tumor-associated immune cell (TIC) score 10% vs. 10%, as assessed by a central laboratory using the investigational Ventana PD-L1 (SP263) Companion Diagnostic (CDx) Assay Stage of disease prior to dCRT: Stage II versus Stage III versus Stage IV 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: Signed Informed Consent Form Age 18 years at time of signing Informed Consent Form Ability to comply with the study protocol, in the investigator’s judgment ECOG Performance Status of 0 or 1 Histologically or cytologically confirmed diagnosis of squamous cell carcinoma of the esophagus Stage IIIVA per American Joint Committee on Cancer/Union for International CancerControl, 8th edition, unresectable locally advanced disease (medically or surgery is declined) prior to dCRT. 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 (5064 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 184 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. 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) Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained after the last dose of chemoradiotherapy and within 14 days prior to randomization. Negative HIV test at screening 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 less than 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 of study treatment, and patients should be willing to continue anti-HBV therapy for the duration of study treatment, and longer per institutional guidelines. 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. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm Exclusion criteria Patients who meet any of the following criteria will be excluded from study entry: Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including antiCTLA-4, antiPD-1, antiPD-L1 and anti-TIGIT therapeutic antibodies Any unresolved toxicity of NCI CTCAE Grade more than or equal to 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 Positive Epstein-Barr virus (EBV) viral capsid antigen IgM test at screening. An EBV polymerase chain reaction (PCR) test should be performed as clinically indicated to screen for active infection or suspected chronic active infection. Patients with a positive EBV PCR test are excluded. Uncontrolled tumor-related pain. Patients requiring pain medication must be on a stable regimen at study entry. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., PleurX) are allowed. Uncontrolled or symptomatic hypercalcemia Active or history of autoimmune disease or immune deficiency History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan History of radiation pneumonitis in the radiation field (fibrosis) is permitted. Active tuberculosis Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment History of malignancy other than esophageal cancer within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer Patients who received endoscopic mucosal resection or dissection for superficial mucosal cancers other than esophageal squamous cell carcinoma (ESCC) within 2 years prior to screening are eligible for the study. Patients with illness or conditions that interfere with their capacity to understand, follow, and/or comply with study procedures Severe infection within 4 weeks prior to randomization, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that, in the opinion of the investigator, could impact patient safety Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to randomization. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study. Prior allogeneic stem cell or solid organ transplantation Treatment with a live, attenuated vaccine (e.g., FluMist) within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during study treatment, within 5 months after the last dose of atezolizumab/placebo or 90 days after the last dose of tiragolumab/placebo, whichever is later Treatment with any other investigational agent, including EGFR inhibitors, with therapeutic intent for esophageal cancer prior to randomization Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin-2 [IL-2]) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to randomization Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antiTNF- agents) within 2 weeks prior randomization or anticipation of need for systemic immunosuppressive medication during study treatment History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins Known hypersensitivity to Chinese hamster ovary cell products or to any component of the tiragolumab or atezolizumab formulation Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment, within 5 months after the final dose of atezolizumab, or within 90 days after the final dose of tiragolumab, whichever is later Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to randomization.