| Protocol No: | ECCT/22/01/01 | Date of Protocol: | 11-08-2021 |
| Study Title: |
A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL TO EVALUATE THE EFFICACY AND SAFETY OF ADJUVANT ATEZOLIZUMAB OR PLACEBO AND TRASTUZUMAB EMTANSINE FOR HER2-POSITIVE BREAST CANCER AT HIGH RISK OF RECURRENCE FOLLOWING PREOPERATIVE THERAPY
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| Study Objectives: |
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab when given in combination with trastuzumab emtansine compared with placebo and trastuzumab emtansine in both the ITT population (all comers) and the PD-L1 positive population (defined as all patients from the ITT population with a centrally assessed PD-L1 positive status [i.e., PD-L1 status of IC1/2/3] at randomization) on the basis of the following endpoint:
IDFS, defined as the time from randomization to the first occurrence of any of the events defined below (whichever occurs first):
The secondary efficacy objective for this study is to evaluate the efficacy of atezolizumab when given in combination with trastuzumab emtansine compared with placebo and trastuzumab emtansine in both the ITT population and PD-L1 positive population on the basis of the following endpoints:
Efficacy will be evaluated in the PRO-evaluable analysis set on the basis of following endpoints:
The safety objective for this study is to evaluate the safety of atezolizumab when given in combination with trastuzumab emtansine compared with placebo and trastuzumab emtansine on the basis of the following endpoints:
The exploratory safety objective for this study is to evaluate the safety of atezolizumab when given in combination with trastuzumab emtansine compared with placebo and trastuzumab emtansine from the patient's perspective, on the basis of the following endpoint:
The pharmacokinetic (PK) objective for this study is to characterize the PK profiles of atezolizumab and trastuzumab emtansine when given in combination on the basis of the following endpoints:
The immunogenicity objective for this study is to evaluate the immune response to atezolizumab and trastuzumab emtansine on the basis of the following endpoints:
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that are predictive of response to atezolizumab and trastuzumab emtansine (i.e., predictive biomarkers), are early surrogates of efficacy, are associated with progression to a more severe disease state (i.e., prognostic biomarkers), are associated with acquired resistance to atezolizumab and trastuzumab emtansine, are associated with susceptibility to developing adverse events or can lead to improved adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence of atezolizumab and trastuzumab emtansine activity (i.e.,
pharmacodynamic biomarkers), or can increase the knowledge and understanding of disease biology and drug safety, on the basis of the following endpoints:
The exploratory health status utility objective for this study is to evaluate health status utility scores of patients treated with atezolizumab when given in combination with trastuzumab emtansine compared with placebo and trastuzumab emtansine on the basis of the following endpoint:
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| Laymans Summary: |
The purpose of this study is to compare the effects, good or bad, of atezolizumab plus trastuzumab emtansine versus placebo plus trastuzumab emtansine in patients with HER2-positive early breast cancer. In this study, the trrial subjects will get either atezolizumab plus trastuzumab emtansine or placebo plus trastuzumab emtansine. A placebo looks like a drug but has no active ingredient.
Atezolizumab is a cancer immunotherapy and binds to a protein called PD-L1, blocking the usual function of PD-L1, in order to help your immune system to recognize and fight off cancer cells. Atezolizumab (Tecentriq→) is approved for the treatment of urothelial carcinoma (a type of bladder cancer), some lung cancers, hepatocellular carcinoma (a type of liver cancer), melanoma (a type of skin cancer), as well as triple-negative breast cancer (which is a breast cancer that is different from the breast cancer you have). However, in this study, atezolizumab is an experimental drug, which means that health authorities have not approved atezolizumab either alone or in combination with trastuzumab emtansine for the treatment of HER2-positive breast cancer.
Trastuzumab emtansine is a drug that combines trastuzumab (Herceptin→), a drug that attaches to HER2 proteins on the surface of cancer cells, and a chemotherapy drug. Combining these drugs means that the chemotherapy drug is delivered specifically to cancer cells with HER2 on their surface and destroys them. Trastuzumab emtansine (Kadcyla®) has been approved for the treatment of HER2-positive breast cancer. However, trastuzumab emtansine is not approved in combination with atezolizumab which is the combination tested in this clinical trial.
This study will evaluate the efficacy, safety, and pharmacokinetics of adjuvant atezolizumab when given in combination with trastuzumab emtansine compared with
placebo and trastuzumab emtansine for patients with residual invasive HER2-positive breast cancer following neoadjuvant taxane-based and HER2-targeted therapy including trastuzumab, who are at high risk of disease recurrence. The primary endpoint for this study is IDFS.
About 1700 people will take part in this study. In Kenya, 20 participants will be enrolled in the study.
This study will last approximately 14 years.
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| Abstract of Study: |
A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL TO EVALUATE THE EFFICACY AND SAFETY OF ADJUVANT ATEZOLIZUMAB OR PLACEBO AND TRASTUZUMAB EMTANSINE FOR HER2-POSITIVE BREAST CANCER AT HIGH RISK OF RECURRENCE FOLLOWING PREOPERATIVE THERAPY
PROTOCOL NUMBER: WO42633
TEST PRODUCTS: Atezolizumab (RO5541267), Trastuzumab emtansine (RO5304020), Trastuzumab (RO0452317)
PHASE: Phase III
RATIONALE
Globally, breast cancer is the second most common invasive malignancy and the most common cause of cancer-related mortality in women. An estimated 2 million new breast cancer cases were diagnosed in 2018 (24% of all cancers in women) and there were over 600,000 breast cancer-related deaths in 2018 (Bray et al. 2018). The majority of breast cancer in the Western world is diagnosed when the cancer is still confined to the breast, with or without locoregional lymph node spread (Minicozzi et al. 2017; Howlader et al. 2020). At these early stages (IIII, early breast cancer [EBC]), the largely asymptomatic disease is usually operable and can be treated with curative intent.
Approximately one in five women diagnosed with EBC has human epidermal growth factor receptor 2 (HER2) positive disease (Wolff et al. 2013). Breast cancers
over-expressing HER2 are the most aggressive, and while current therapies have significantly improved patient outcomes, up to 1 in 4 women with HER2-positive EBC experience recurrence or death within 1011 years of diagnosis, despite targeted treatment approaches (Perez et al. 2014; Slamon et al. 2016; Cameron et al. 2017).
Patients treated with neoadjuvant trastuzumab and pertuzumab with standard chemotherapy have a 5-year disease-free survival (DFS) rate of 84% (Gianni et al.
2016). Patients with HER2-positive EBC who have residual tumor present in the breast and/or axillary lymph nodes following neoadjuvant therapy achieved significantly improved invasive disease-free survival (IDFS) with adjuvant trastuzumab emtansine compared with trastuzumab (hazard ratio [HR] 0.50; 95% CI: 0.39 to 0.64; p 0.001). The estimated percentage of patients free of invasive disease at 3 years from randomization was 88.3% with trastuzumab emtansine and 77.0% with trastuzumab (von Minckwitz et al. 2019).
Patients who relapse with metastatic or unresectable disease are generally incurable.
Overall (i.e., all subtypes of breast cancer, including HER2-negative disease), patients with metastatic disease have a median survival of approximately 24 months and a 5-year life expectancy of 1826% in the United States and Europe (Sant et al. 2003; Howlader et al. 2020). With the advent of pertuzumab, life expectancy for patients with metastatic HER2-positive breast cancer has greatly improved with an observed median
overall survival (OS) of 56.5 months in the CLEOPATRA study. Nevertheless, more than 50% of patients receiving first-line treatment with trastuzumab, pertuzumab, and a taxane for metastatic disease die within 5 years (Swain et al. 2020). HER2-positive breast cancer is estimated to account for approximately 6,0008,000
deaths per year in the United States, 19,00026,000 deaths per year in Europe, and approximately 78,000104,000 deaths per year globally (DeSantis et al. 2015; Ferlay et al. 2015; Howlader et al. 2020). Because metastatic disease is currently incurable, improving the results of initial therapy, when the disease is still localized to the breast and regional lymph nodes but without distant metastases, offers the best chance of cure.
For patients who are not cured, improved initial therapy may produce meaningful delays in disease recurrence and death.
OBJECTIVES AND END POINTS
The primary efficacy objective for this study is to evaluate the efficacy of atezolizumab when given in combination with trastuzumab emtansine compared with placebo and trastuzumab emtansine in both the ITT population (all comers) and the PD-L1 positive population (defined as all patients from the ITT population with a centrally assessed PD-L1 positive status [i.e., PD-L1 status of IC1/2/3] at randomization) on the basis of the following endpoint:
IDFS, defined as the time from randomization to the first occurrence of any of the events defined below (whichever occurs first):
The secondary efficacy objective for this study is to evaluate the efficacy of atezolizumab when given in combination with trastuzumab emtansine compared with placebo and trastuzumab emtansine in both the ITT population and PD-L1 positive population on the basis of the following endpoints:
Efficacy will be evaluated in the PRO-evaluable analysis set on the basis of following endpoints:
The safety objective for this study is to evaluate the safety of atezolizumab when given in combination with trastuzumab emtansine compared with placebo and trastuzumab emtansine on the basis of the following endpoints:
Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0).
The exploratory safety objective for this study is to evaluate the safety of atezolizumab when given in combination with trastuzumab emtansine compared with placebo and trastuzumab emtansine from the patient's perspective, on the basis of the following endpoint:
The pharmacokinetic (PK) objective for this study is to characterize the PK profiles of atezolizumab and trastuzumab emtansine when given in combination on the basis of the following endpoints:
The immunogenicity objective for this study is to evaluate the immune response to atezolizumab and trastuzumab emtansine on the basis of the following endpoints:
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that are predictive of response to atezolizumab and trastuzumab emtansine (i.e., predictive biomarkers), are early surrogates of efficacy, are associated with progression to a more severe disease state (i.e., prognostic biomarkers), are associated with acquired resistance to atezolizumab and trastuzumab emtansine, are associated with susceptibility to developing adverse events or can lead to improved adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence of atezolizumab and trastuzumab emtansine activity (i.e.,
pharmacodynamic biomarkers), or can increase the knowledge and understanding of disease biology and drug safety, on the basis of the following endpoints:
The exploratory health status utility objective for this study is to evaluate health status utility scores of patients treated with atezolizumab when given in combination with trastuzumab emtansine compared with placebo and trastuzumab emtansine on the basis of the following endpoint:
STUDY DESIGN
Study WO42633 is a Phase III, two-arm, randomized, double-blind, placebo-controlled study in patients with HER2-positive primary breast cancer who have received preoperative chemotherapy and HER2-directed therapy, including trastuzumab followed by surgery, with a finding of residual invasive disease in the breast and/or axillary lymph nodes. Patients will be randomized to one of the following treatment arms in a 1:1 ratio:
NUMBER OF PATIENTS
Approximately 1700 patients who have pathologically documented residual invasive disease in the breast and/or axillary lymph nodes following completion of preoperative therapy will be enrolled in the study over a period of approximately 45 months. Target enrollment is based on the assumption that 50% of patients will have PD-L1 positive tumors (defined as centrally confirmed PD-L1 status of IC1/2/3); enrollment in the study will be monitored to ensure that the anticipated PD-L1 prevalence is achieved. Additionally, enrollment of patients with hormone receptor-positive disease will be capped at 50%
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