Health Condition 1: C509- Malignant neoplasm of breast of unspecified site
Conditions
Interventions
Intervention1: Trastuzumab Deruxtecan (T-DXd): Compared with investigator’s choice chemotherapy
Control Intervention1: Standard of care: Capecitabine, Paclitaxel and Nab-paclitaxel
Sponsors
AstraZeneca AB
Eligibility
Inclusion criteria
Inclusion criteria: 1 Male or female patients: a) = 18 years of age – applicable for all countries participating in the study except Japan, b) = 20 years of age – applicable for Japan only 2 Pathologically documented breast cancer that: a) Is advanced or metastatic b) Has a history of HER2-low or negative expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested) or IHC 0 (ISH- or untested) with a validated assay c) Patients with historical HER2-low or HER2 IHC 0 expression must be confirmed by central laboratory testing to have HER2 low expression or HER2 IHC >0 0 o If a patient has had multiple historical/local HER2 results, the most recent result will be compared with the central laboratory HER2 results to confirm eligibility. o The most recent historical/local HER2 result that will be used to compare with the central laboratory HER2 result must be from metastatic disease or later. o If most recent local HER2 testing only classified the patient’s tumor as HER2 negative (IHC status not available), eligibility will be determined by the central laboratory testing results. d) Was never previously reported as HER2-positive (IHC 3+ or ISH+) as per ASCO/CAP guidelines. e) Is documented as HR+ (either ER and/or PgR positive [ER or PgR =1%]) per ASCO/CAP guidelines (Hammond et al, 2010) in the metastatic setting. If a patient has had multiple ER/PgR results after metastatic disease, the most recent test result will be used to confirm eligibility 3 Must have an adequate tumor tissue sample available for assessment of HER2 by central laboratory and other exploratory biomarker analyses and is preferred in FFPE blocks based on a mandatory FFPE tumor sample obtained at the time of metastatic disease or later; the most recently collected pre-randomization tumor sample from the time of metastatic disease or later that meets the tissue requirements specified in Section 8.6.1 is required. If no archival specimens are available, a newly acquired biopsy specimen is acceptable. (see Section 8.6.1 and the laboratory manual for additional details). 4 ECOG performance status of 0 or 1 5 Radiologic or objective evidence of disease progression on or after the last systemic therapy prior to starting study treatment 6 Must have had disease progression on at least 2 previous lines of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors) administered for the treatment of metastatic disease. Of note: a) Single agent anti-CDK4/6 therapy for the treatment of metastatic disease is considered a line of therapy b) Disease progression within 24 months of starting adjuvant ET is considered a line of therapy c) Any progression after completing a course of adjuvant ET will not be considered a line of therapy d) Changes in dosing schedules, or discontinuations/re-starting of the same drugs or the addition of a targeted therapy to an ET without progression (e.g., adding a CDK4/6 to a current aromatase inhibitor regimen) will not be considered separate lines of therapy. 7 No prior chemotherapy for advanc
Exclusion criteria
Exclusion criteria: Patients must NOT meet the following criteria at screening: 1. Ineligible for all options in the investigator’s choice chemotherapy arm 2. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, uncontrolled or significant cardiovascular disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent. 3. Uncontrolled or significant cardiovascular disease includes any of the following: a. Patients with a medical history of myocardial infarction within 6 months before randomization or symptomatic CHF (NYHA Class II to IV). Patients with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial infarction related symptoms, should have a cardiologic consultation before enrollment to rule out myocardial infarction. b. Uncontrolled hypertension c. Uncontrolled and/or clinically important cardiac arrhythmias d. Corrected QT interval by Fredericia’s method (QTcF) prolongation to >470 ms (females) or >450 ms (male) based on average of screening triplicate 12-lead electrocardiogram (ECG) 4. Has as a history of (non-infectious) ILD/pneumonitis, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. 5. Patients with prior use of immunosuppressive medication within 14 days prior to first study dose, except for intranasal and inhaled corticosteroids or systemic corticosteroids at doses less than 10 mg/day of prednisone or equivalent. 6. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within three months prior to study enrollment, severe asthma, severe chronic obstructive pulmonary disorder [COPD], restrictive lung disease, significant pleural effusion etc.), and any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (i.e., rheumatoid arthritis, Sjogren’s syndrome, sarcoidosis etc.), and/or prior pneumonectomy. 7. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals 8. Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment. 9. Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. Patients positive for hepatitis C antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Participants should be tested for HIV prior to randomization if required by local regulations or by the IRB/IEC. 10. Receipt of live, attenuated vaccine within 30 days prior to the first dose of study treatment. Note
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| PFS by BICR according to RECIST 1.1 in the HR positive, HER2 low population Timepoint: PFS in the HER2 low population and ITT population will be tested once, when PFS reaches approximately 65 percent maturity (456 events) in the HER2 low population. This is estimated to occur 29 months after the first patient is randomized (4 months after randomization is completed) assuming a non-uniform accrual of patients with a duration of 25 months. At this time, it is expected that at least 553 events (65 percent maturity) will have been observed in the ITT population | — |
Secondary
| Measure | Time frame |
|---|---|
| I. To assess the efficacy of T DXd compared with investigators choice chemotherapy in terms of OS in the HR PLUS, HER2-low population ii. OS in the ITT population (HER2 IHC greater than 0 less than 1 PLUS and HER2-low) Timepoint: ii. Approximately 44 months after the first patient is randomized (392 OS events in the HER2-low population and 477 OS events have been observed in the ITT population at this time) iii. Approximately 57 months after the first patient is randomized (489 OS events in the HER2-low population and 594 OS events have been observed in the ITT population) ;I. To assess the efficacy of T DXd compared with investigators choice chemotherapy in terms of OS in the HR PLUS, HER2-low population ii. OS in the ITT population (HER2 IHC greater than 0 less than 1 PLUS and HER2-low)Timepoint: OS in the HER2-low population and ITT population will be tested at two interim and one final analysis as described below I. Approximately 29 months after the first patient is randomized (216 OS events in the HER2 low population and 263 OS events have been observed in the ITT population) ;To assess the efficacy of T DXd compared with investigators choice chemotherapy in terms of PFS by BICRTimepoint: Approximately 29 months after first patient is randomized (456 events in the HER2 low population and at least 553 events have been observed in the ITT population) | — |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Denmark, France, Germany, Hungary, India, Israel, Italy, Japan, Mexico, Netherlands, Poland, Portugal, Republic of Korea, Russian Federation, Saudi Arabia, Spain, Sweden, Taiwan, United Kingdom, United States of America
Contacts
Public ContactMr Sandeep AV
AstraZeneca Pharma India Ltd
Outcome results
None listed