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Protocol NumberDS8201-A-U303
NCT Number(ClinicalTrials.gov Identfier)NCT03734029

2019-02-01 - 2023-08-04

Phase III

Recruiting3

Terminated1

ICD-10C50.911

Malignant neoplasm of unspecified site of right female breast

ICD-10C50.912

Malignant neoplasm of unspecified site of left female breast

ICD-10C50.919

Malignant neoplasm of unspecified site of unspecified female breast

ICD-10Z51.12

Encounter for antineoplastic immunotherapy

ICD-9174.9

Malignant neoplasm of female breast, unspecified

A Phase 3, Multicenter, Randomized, Open-label, Active Controlled Trial of DS-8201a, an Anti-HER2-antibody Drug Conjugate (ADC), Versus Treatment of Physician's Choice for HER2-low, Unresectable and/or Metastatic Breast Cancer Subjects

  • Trial Applicant

    IQVIA RDS Taiwan Ltd.

  • Sponsor

    Daiichi Sankyo Inc.

  • Trial scale

    Multi-Regional Multi-Center

  • Update

    2025/08/20

Investigators and Locations

Principal Investigator Wei-Pang Chung Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Ling-Ming Tseng Division of General Surgery
Taipei Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator YEN-SHEN LU Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Ming-Feng Hou Division of General Surgery
Kaohsiung Medical Univeristy Chung-Ho Memorial Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Condition/Disease

Breast Cancer

Objectives

Primary Objectives The primary objective is to compare the PFS benefit of DS-8201a to physician’s choice in HER2-low, HR-positive breast cancer, based on blinded independent central review (BICR). Secondary Objectives The secondary objectives are: To investigate the efficacy of DS-8201a compared to physician’s choice on the following parameters (definitions of these endpoints are included in Section 7.1.2):  PFS in HR-positive subjects, based on Investigator assessment  Overall survival (OS) in HR-positive subjects  Confirmed objective response rate (ORR), based on BICR and Investigator assessment in HR-positive subjects  Duration of response (DoR), based on BICR and Investigator assessment in HRpositive subjects  PFS, OS, confirmed ORR, and DoR in all subjects, regardless of HR status  To determine PK of DS-8201a  To evaluate safety of DS-8201a compared to physician’s choice  To evaluate Health Economics and Outcomes Research (HEOR) endpoints for DS-8201a compared to physician’s choice

Test Drug

trastuzumab deruxtecan (T-DXd)

Active Ingredient

trastuzumab deruxtecan (T-DXd)

Dosage Form

Lyophilized powder for injection

Dosage

100 mg

Endpoints

Study Endpoints
The efficacy endpoints will be based on central assessments unless otherwise stated.

Primary Efficacy Endpoint
The primary efficacy endpoint is PFS, based on BICR.

Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
 PFS, based on Investigator assessment
 OS
 Confirmed ORR, based on BICR and Investigator assessment
 DoR, based on BICR and Investigator assessment

Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are:
 CBR, based on BICR and Investigator assessment
 DCR, based on BICR and Investigator assessment
 TTR, based on BICR and Investigator assessment.

Health Economic and Outcomes Research Endpoints
The HEOR endpoints include:
 European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaires (QLQ)
 C30
 BR45
 EuroQol 5 dimensions 5 levels [of severity] (EQ-5D-5L)
 Hospitalization-related endpoints

Pharmacokinetic/Biomarker Endpoints
Pharmacokinetic Endpoints
The PK endpoints include:
 Serum concentrations of DS-8201a, total anti-HER2 antibody, and MAAA-1181a

Biomarker Endpoints
The biomarker endpoints include:
 Serum biomarkers (eg, extracellular domain of HER2 [HER2ECD])
 Other potential biomarkers (eg, deoxyribonucleic acid [DNA] profiling in cell free
DNA [cfDNA], RNA expression profiling, mutations)

Safety Endpoints
The safety endpoints include:
 Serious adverse events (SAEs)
 TEAEs, graded according to the National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE) version 5.0
 AESIs
 Discontinuations due to AEs
 Physical examination findings
 Eastern Cooperative Oncology Group performance status (ECOG PS)
 Vital sign measurements
 Standard clinical laboratory parameters
 Electrocardiogram (ECG) parameters
 Echocardiogram (ECHO)/multigated acquisition (MUGA) scan findings
 Anti-drug antibodies (ADAs)

Inclution Criteria

1. Must be competent and able to comprehend, sign, and date an Institutional Review Board
(IRB) or Institutional Ethics Committee (IEC) approved ICF before performance of any
study-specific procedures or tests.
2. Men or women ≥18 years old. (Please follow local regulatory requirements if the legal
age of consent for study participation is >18 years old.)
3. Pathologically documented breast cancer that:
a. Is unresectable or metastatic.
b. Has a history of low HER2 expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested).
c. Assessed as low HER2 expression, defined as IHC 2+/ISH- or IHC 1+ according to
ASCO-CAP 2018 guidelines (adapted by Daiichi Sankyo Inc. and Ventana – please
see the study laboratory manual for details) evaluated at a central laboratory.
d. Is HR-positive or HR-negative. After ~60 HR-negative subjects are enrolled, further
enrollment will be limited to only subjects who are HR-positive per ASCO-CAP 2018
guidelines (adapted by Daiichi Sankyo Inc. and Ventana – please see the study
laboratory manual for details) (positive for estrogen receptor or progesterone receptor
if finding of ≥1% of tumor cell nuclei are immunoreactive).
e. Is documented refractory to endocrine therapy, defined as having progressed on at
least 1 endocrine therapy and determined by the Investigator that subject would no
longer benefit from further treatment with endocrine therapy.
f. If HR-positive, has or has not been treated with a CDK4/6 inhibitor. After ~240 HRpositive subjects have been enrolled who have not had prior therapy with a CDK4/6
inhibitor, further enrollment of HR-positive subjects will be limited to subjects who
have had prior therapy with a CDK4/6 inhibitor.
g. Has been treated with at least 1 and at most 2 prior lines of chemotherapy in the
recurrent or metastatic setting. If recurrence occurred within 6 months of
(neo)adjuvant chemotherapy, (neo)adjuvant therapy would count as 1 line of
chemotherapy. Targeted agents (such as mTOR inhibitors, PARP inhibitors, PD-L
inhibitors, or PD-L1 inhibitors) and endocrine therapies on their own do not
contribute to the count of prior lines of chemotherapy, although regimens with such
agents in combination with chemotherapy would still count as 1 line of chemotherapy.
h. Was never previously HER2-positive (IHC 3+ or ISH+) on prior pathology testing
(per ASCO-CAP 2018 guidelines [adapted by Daiichi Sankyo Inc. and Ventana –
please see the study laboratory manual for details]).
i. Was never previously treated with anti-HER2 therapy.
4. Documented radiologic progression (during or after most recent treatment).
5. Must have an adequate archival tumor sample available for assessment of HER2 status by
central laboratory (based on most recent available tumor tissue sample). If archival tissue
is not available, a fresh biopsy is required.
6. All subjects must have a recent tumor sample after the most recent treatment regimen or
agree to undergo a tissue biopsy prior to randomization.
7. Presence of at least 1 measurable lesion based on computed tomography (CT) or
magnetic resonance imaging (MRI) per modified Response Evaluation Criteria in Solid
Tumors (mRECIST) version 1.1 (see Section 17.6).17
8. ECOG PS 0 or 1.
9. LVEF ≥50% within 28 days prior to randomization.
10. Adequate bone marrow function within 14 days before randomization, defined as:
 Platelet count ≥100,000/mm3
(Platelet transfusion is not allowed within 1 week prior
to Screening assessment)
 Hemoglobin level ≥9.0 g/dL (red blood cell transfusion is not allowed within 1 week
prior to Screening assessment)
 Absolute neutrophil count ≥1500/mm3
(granulocyte colony-stimulating factor
administration is not allowed within 1 week prior to Screening assessment)
11. Adequate renal function within 14 days before randomization, defined as:
 Creatinine clearance ≥30 mL/min, as calculated using the Cockcroft-Gault equation
(see Section 17.2; [{140 – age in y} × {weight in kg}] divided by [{72 × serum
creatinine in mg/dL} multiply by 0.85 if female]).
12. Adequate hepatic function within 14 days before randomization, defined as:
 Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤5 × upper limit of normal (ULN)
 Total bilirubin ≤1.5 × ULN if no liver metastases or <3 × ULN in the presence of
documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline
13. Adequate blood clotting function within 14 days before randomization, defined as:
 International normalized ratio/prothrombin time and activated partial thromboplastin time ≤1.5 × ULN
14. Male and 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 4.5 months after the last dose of DS-8201a or according to
the locally approved labels for the physician’s choice treatments.

Methods considered
as highly effective methods of contraception include:
 Combined (estrogen and progestogen containing) hormonal contraception associated
with inhibition of ovulation:
 Oral
 Intravaginal
 Transdermal
 Progestogen-only hormonal contraception associated with inhibition of ovulation:
 Oral
 Injectable
 Implantable
 Intrauterine device
 Intrauterine hormone-releasing system
 Bilateral tubal occlusion
 Vasectomized partner
 Complete sexual abstinence defined as refraining from heterosexual intercourse
during and upon completion of the study and for at least 4.5 months after the last dose
of study treatment. Periodic abstinence (calendar, symptothermal, postovulation
methods) is not an acceptable method of contraception.
15. Male subjects must not freeze or donate sperm starting at Screening and throughout the
study period, and at least 4.5 months after the final study treatment administration or
according to the locally approved labels for the physician’s choice treatments.
Preservation of sperm should be considered prior to enrollment in this study.
16. Female subjects must not donate ova, or retrieve for their own use, from the time of
Screening and throughout the study treatment period, and for at least 4.5 months after the
final study treatment administration or according to the locally approved labels for the
physician’s choice treatments.

Exclusion Criteria

1. Ineligible for all 5 of the options in the physician’s choice arm either because of previously having received treatment in the metastatic setting with the comparator or having a contraindication to treatment.
2. Prior treatment with antibody drug conjugate that consists of an exatecan derivative that is a topoisomerase I inhibitor.
3. Uncontrolled or significant cardiovascular disease, including any of the following:
a. History of myocardial infarction within 6 months before randomization, troponin
levels consistent with myocardial infarction as defined according to the manufacturer 28 days prior to randomization
b. History of symptomatic congestive heart failure (New York Heart Association Class II to IV)
c. Corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (male)
based on average of Screening triplicate 12 lead ECGs
4. Has a history of (noninfectious) ILD/pneumonitis that required steroids, has current
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
5. Has spinal cord compression or clinically active central nervous system metastases,
defined as untreated or symptomatic, or requiring therapy with corticosteroids or
anticonvulsants to control associated symptoms.
 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.
6. Has multiple primary malignancies within 3 years, except adequately resected
nonmelanoma skin cancer, curatively treated in situ disease, or contralateral breast cancer.
7. Has a history of severe hypersensitivity reactions to either the drug substances or inactive
ingredients in the drug product.
8. Has a history of severe hypersensitivity reactions to other monoclonal antibodies.
9. Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
10. Substance abuse or medical conditions such as clinically significant cardiac or pulmonary
diseases or psychological conditions, that would, in the opinion of the Investigator,
increase the safety risk to the subject or interfere with the subject’s participation in the
clinical study or evaluation of the clinical study results.
11. Social, familial, or geographical factors that would interfere with study participation or follow-up.
12. Has known human immunodeficiency virus (HIV) infection or active hepatitis B or C
infection. Subjects should be tested for HIV prior to randomization if required by local
regulations or IRB/IEC.
13. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other
than alopecia) not yet resolved to Grade ≤1 or baseline. Subjects with chronic Grade 2
toxicities may be eligible per the discretion of the Investigator after consultation with the
Sponsor Medical Monitor or designee (eg, Grade 2 chemotherapy-induced neuropathy).
14. Therapeutic radiation therapy or major surgery within 4 weeks before study treatment or
palliative stereotactic radiation therapy within 2 weeks before study treatment.
15. Systemic treatment with anticancer therapy, antibody-based therapy, retinoid therapy, or
hormonal therapy within 3 weeks before study treatment; or treatment with nitrosoureas
or mitomycin C within 6 weeks before study treatment; or treatment with small-molecule
targeted agents within 2 weeks, or 5 half-lives, whichever is longer.
16. Current treatment with strong cytochrome P450 (CYP3A4) and organic anion
transporting polypeptide (OATP) inhibitors (see Section 17.5) (washout period of
≥3 elimination half-lives of the inhibitor/antibody is required).
17. Participation in a therapeutic clinical study within 3 weeks before study treatment (for
small-molecule targeted agents, this nonparticipation period is 2 weeks or 5 half-lives,
whichever is longer), current participation in other therapeutic investigational procedures
or prior participation in this investigational trial.
18. Is pregnant or breastfeeding, or planning to become pregnant.
19. Subject must not be study site personnel or Sponsor employee directly involved in the
clinical trial, or an immediate family member of someone directly involved.
20. Otherwise considered inappropriate for the study by the Investigator.

The Estimated Number of Participants

  • Taiwan

    14 participants

  • Global

    540 participants

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