Phase 3 Multicenter Randomized Study of Trastuzumab Deruxtecan vs. Ado-Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer Post-Trastuzumab and Taxane Treatment
- Trial ID
- 2024-511204-16-00
- Protocol
- DS8201-A-U302
- Sponsor
- Daiichi Sankyo Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **progression-free survival (PFS)** benefit of trastuzumab deruxtecan to T-DM1 in patients with HER2-positive, unresectable, and/or metastatic breast cancer who have previously been treated with trastuzumab and taxane. This objective is clinically relevant as it aims to determine the efficacy of trastuzumab deruxtecan in delaying disease progression, which is a critical factor in the management of metastatic breast cancer.
Secondary objectives include:
- Comparing the overall survival (OS) benefit of trastuzumab deruxtecan to T-DM1.
- Evaluating the efficacy of trastuzumab deruxtecan compared to T-DM1 in terms of confirmed objective response rate (ORR) and duration of response (DoR).
- Further determining the pharmacokinetics (PK) of trastuzumab deruxtecan.
- Evaluating the safety profile of trastuzumab deruxtecan compared to T-DM1.
- Assessing Health Economic and Outcomes Research (HEOR) endpoints for trastuzumab deruxtecan compared to T-DM1.
Participants
The clinical trial involves a total of **177 participants** diagnosed with **metastatic breast cancer**. The study population includes both male and female adults aged 18 years and older, with a focus on individuals who have previously been treated with trastuzumab and taxane. Participants were selected based on their confirmed HER2-positive status, as determined by central laboratory assessment, and documented radiologic progression. The trial includes individuals with adequate renal and hepatic function, as defined by specific clinical parameters. Participants are required to adhere to strict contraceptive measures due to the potential teratogenic effects of the investigational drugs. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial population includes a vulnerable group, indicating the inclusion of individuals who may require additional ethical considerations during the study. The sponsor has not provided further details regarding the selection process or additional lifestyle factors.
Plans and Procedures
The clinical trial is a **Phase 3**, multicenter, randomized, open-label, active-controlled study designed to evaluate the efficacy of **trastuzumab deruxtecan** (DS-8201a) compared to **ado-trastuzumab emtansine** (T-DM1) in subjects with **HER2-positive metastatic breast cancer**. The primary objective is to assess progression-free survival (PFS) as determined by blinded independent central review (BICR), with overall survival (OS) as a key secondary endpoint. The trial is expected to run from April 2019 to November 2025, with a maximum treatment period of 105 weeks for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented HER2-positive status, and previous treatment history. Following randomization, participants will receive either DS-8201a or T-DM1 via **intravenous infusion**. Regular follow-up visits will be scheduled to monitor treatment response, safety, and any adverse events. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and ensuring post-treatment safety.
Participant involvement is anticipated to last up to 105 weeks, contingent upon individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant adverse reactions, disease progression, or withdrawal of consent. The trial is not classified as low intervention, and it adheres to rigorous standards to ensure the validity and reliability of the results.
Treatment
The clinical trial involves the administration of two experimental medications for the treatment of **HER2-positive, unresectable and/or metastatic breast cancer**. The first medication, **Kadcyla**, is a 100 mg powder for concentrate for solution for infusion, containing the active substance **trastuzumab emtansine**. This pharmaceutical form is prepared as a solution for infusion and is administered via **intravenous infusion**. The dosage is set at a maximum of 3.6 mg/kg, with the treatment period extending up to 105 days. The medication is produced by Roche Registration GmbH and is not a pediatric formulation. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.
The second experimental medication, **DS-8201a**, contains the active substance **trastuzumab deruxtecan** and is also formulated as a solution for infusion. This medication is administered through **intravenous infusion** with a maximum dosage of 5.4 mg/kg. The treatment duration is similarly capped at 105 days. DS-8201a is manufactured by Daiichi Sankyo, Inc. and is not intended for pediatric use. As with Kadcyla, participant compliance with the dosing regimen is closely monitored to maintain the integrity of the trial results.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study. The trial is designed to compare the progression-free survival benefit of trastuzumab deruxtecan to T-DM1 in subjects who have previously been treated with trastuzumab and taxane. The study is conducted in a multicenter, randomized, open-label, active-controlled format, ensuring rigorous evaluation of the therapeutic efficacy of the investigational drugs.
Efficacy
Efficacy in this clinical trial will be assessed primarily through **progression-free survival (PFS)**, as determined by a blinded independent central review (BICR). This endpoint is critical for evaluating the benefit of trastuzumab deruxtecan compared to ado-trastuzumab emtansine (T-DM1) in subjects with HER2-positive, unresectable, and/or metastatic breast cancer who have been previously treated with trastuzumab and taxane. The key secondary efficacy endpoint is overall survival (OS), which will provide additional insights into the treatment's impact on patient longevity.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adults ≥18 years old. (Please follow local regulatory requirements if the legal age of consent for study participation is >18 y old.) • Pathologically documented breast cancer that: - is unresectable or metastatic - has confirmed HER2 positive expression as determined according to American Society of Clinical Oncology – College of American Pathologists guidelines evaluated at a central laboratory. - was previously treated with trastuzumab and taxane in the advanced/metastatic setting or progressed within 6 mo after neoadjuvant or adjuvant treatment involving a regimen including trastuzumab and taxane. • Documented radiologic progression (during or after most recent treatment or within 6 mo after completing adjuvant therapy). • Subjects must be HER2 positive as confirmed by central laboratory assessment of most recent tumor tissue sample available. • Female subjects of reproductive/childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 7 mo after the last dose of trastuzumab deruxtecan and 7 mo after the last dose of T-DM1. Male subjects must agree to inform all potential female partners that they are participating in a clinical trial of a drug that may cause birth defects. Male subjects must also agree to either avoid intercourse or that they and/or any female partners of reproductive / childbearing potential will use a highly effective form of contraception during and upon completion of the study and for at least 4.5 mo after the last dose of trastuzumab deruxtecan or 4 mo after the last dose of T-DM1. • Adequate renal function, defined as: - Creatinine clearance ≥ 30 mL/min, as calculated using the Cockcroft-Gault equation • Adequate hepatic function, defined as: - Total bilirubin ≤ 1.5 × upper limit of normal (ULN) if no liver metastases or < 3 × ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline and - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤5 × ULN.
Exclusion Criteria
- Prior treatment with an anti-HER2 ADC (such as T-DM1) in the metastatic setting. Prior treatment in the adjuvant/neo-adjuvant setting would be allowed if progression of disease did not occur within 12 mo of end of adjuvant therapy. • Uncontrolled or significant cardiovascular disease, including any of the following: - History of myocardial infarction within 6 mo before randomization - History of symptomatic congestive heart failure (New York Heart Association Class II to IV) - Troponin levels consistent with myocardial infarction as defined according to the manufacturer within 28 d prior to randomization - Corrected QT interval prolongation to > 470 ms (females) or > 450 ms (male) based on average of Screening triplicate 12 lead electrocardiogram (ECG) - Left ventricular ejection fraction (LVEF) < 50% within 28 d prior to randomization • Has a history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening. • Spinal cord compression or clinically active central nervous system (CNS) 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. • Prior participation in a study involving an antibody drug conjugate (ADC) produced by Daiichi Sankyo.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 08 Apr 2019 | 5 |
 France | Not Recruiting | 08 Apr 2019 | 23 |
 Italy | Not Recruiting | 08 Apr 2019 | 19 |
 Spain | Not Recruiting | 08 Apr 2019 | 16 |
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 |
|---|---|---|---|---|---|---|
DS-8201a | Test | SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 5.4 | 105 | PRD5308994 |
Kadcyla 100 mg powder for concentrate for solution for infusion. | Comparator | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 3.6 | 105 | PRD974894 |