E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Unresectable/metastatic breast cancer with human epidermal growth factor receptor 2 (HER2)-positive expression |
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E.1.1.1 | Medical condition in easily understood language |
advanced-stage breast cancer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the progression-free survival (PFS) benefit of trastuzumab deruxtecan to T-DM1for HER2-positive, unresectable and/or metastatic breast cancer subjects previously treated with trastuzumab and taxane. |
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E.2.2 | Secondary objectives of the trial |
Key Secondary Objective: To compare the overall survival (OS) benefit of trastuzumab deruxtecan to T-DM1. Other Secondary Objectives: • To evaluate efficacy of trastuzumab deruxtecan compared to T-DM1 on: - Confirmed objective response rate (ORR); - Duration of response (DoR). • To further determine PK of trastuzumab deruxtecan; • To further evaluate safety of trastuzumab deruxtecan compared to TDM1; • To evaluate Health Economic and Outcomes Research (HEOR) endpoints for trastuzumab deruxtecan compared to T-DM1. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
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E.4 | Principal 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 an antibody drug conjugate (ADC) study sponsored by Daiichi Sankyo. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is PFS as determined by blinded independent central review (BICR). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
An interim and a final analysis for PFS is planned in this trial. The interim analysis will be performed when approximately 234 BICR-assessed PFS events (70% information fraction) have been observed. If the trial is not statistically significant at this interim analysis, the final PFS analysis will be performed after observing 335 BICR-assessed PFS events. |
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E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoint is OS. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Two interim analyses and a final analysis of OS are planned. The first OS interim analysis is planned at time of the PFS interim analysis, and the second OS interim analysis is planned at time of the final PFS analysis. Approximately 96 and 153 of the planned 250 OS events (38.4% and 61.2% of information fractions) will be expected to be documented by time of the first and the second OS interim analyses, respectively. Final OS analysis is planned after approximately 250 OS events have been documented. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 13 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 79 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Brazil |
Canada |
China |
Hong Kong |
Japan |
Korea, Republic of |
Taiwan |
United States |
France |
Spain |
Germany |
Italy |
Belgium |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study hypothesis-testing period is defined as the date when approximately 250 OS events have been observed. The study closure is defined as the date when the last subject discontinues study treatment and applicable follow-up occurs, or the study is ended by the Sponsor. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 27 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 69 |