Trastuzumab Deruxtecan (T-DXd) for Subjects with Hormone Receptor-negative and Hormone Receptor-positive HER2-low or HER2 IHC0 Breast Cancer (BC)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Daiichi Sankyo Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

4 Sep 2024 → ongoing

Decision date (initial)

2023-12-11

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Daiichi Sankyo, Inc

External identifiers

EU CT number

2023-505616-38-00

ClinicalTrials.gov

NCT05950945

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the efficacy of T-DXd treatment in subjects with unresectable and/or metastatic BC among the four cohorts. Outcome Measure: TTNT - time from the start of T-DXd to initiation of subsequent anticancer treatment or death due to any cause.

Secondary objectives 5

1. To evaluate the efficacy of T-DXd in subjects with unresectable and/or metastatic BC among the four cohorts. Outcome Measure: Real world PFS – time from start of T-DXd to time of disease progression per investigator assessment based on RECIST version 1.1 or death due to any cause.
2. To evaluate the efficacy of T-DXd in subjects with unresectable and/or metastatic BC among the four cohorts. Outcome Measure: TTD for any reason - time from start of T-DXd to discontinuation of T-Dxd or death.
3. To evaluate the efficacy of T-DXd in subjects with unresectable and/or metastatic BC among the four cohorts. Outcome Measure: ORR - subjects with an objective report per investigator assessment based on RECIST version 1.1.
4. To access the safety and tolerability of T-DXd in subjects with unresectable and/or metastatic BC among the four cohorts. Outcome Measure: Subjects with TEAEs collected between first dose and database lock and analysis of other safety parameters.
5. To evaluate HEOR endpoints including PROs, for subjects treated with T-DXd in subjects with unresectable and/or metastatic BC among the four cohorts.

Conditions and MedDRA coding

Unresectable and/or Metastatic HER2-low or HER2 Immunohistochemistry (IHC) 0 Breast Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Subject must sign and date the main ICF prior to the start of any study-specific qualification procedures.
2. Adults ≥18 years or the minimum legal adult age (whichever is greater) at the time the ICF is signed.
3. Must agree to provide a newly obtained or archival baseline biopsy from primary and/or metastatic lesion. All subjects must provide a formalin-fixed paraffin-embedded (FFPE) tumour sample that meets the tissue requirements for tissue-based analysis (including but not restricted/limited to IHC staining to determine HER2 expression, ISH staining when necessary for HER2-low status, and other predictive biomarkers as well as tumour mutational analysis). A newly acquired sample from a fresh biopsy will be used if available; however, submission of the subject’s most recent biopsy prior to the date of Screening and after the subjects’ last treatment regimen as per ASCO CAP 2018 guidelines is permitted for testing in a local laboratory. This archival sample for Tissue Screening must have been obtained post last line of systemic therapy. If a previously collected sample does not have sufficient material for a minimum of 15 × 4-micron sections (or block equivalent), a fresh biopsy must be collected.
4. Pathologically documented BC tumour that: a. Is unresectable or metastatic. b. Is hormone receptor-negative or hormone receptor-positive. c. Has confirmed HER2 IHC 1+ or IHC 2+/ISH- (HER2-low) status or HER2 IHC0 status as determined according to ASCO CAP 2018 guidelines based on sample collected during Tissue Screening as described above in Inclusion Criterion No. 3. d. Was never previously HER2-positive (IHC 3+ or IHC 2+/ISH+) on prior pathology testing (per ASCO CAP guidelines). e. Was never previously treated with anti-HER2 therapy in the metastatic setting.
5. a. Cohorts 1,2 and 4: hasHas had at least one and up to two prior lines of therapy in the metastatic setting. Targeted agents (such as mTOR inhibitors, PARP inhibitors, PD-1 inhibitors, PD-L1 inhibitors, histone deacetylase inhibitors, or CDK4/6 inhibitors) or endocrine therapy count as a line of therapy. b.a. Cohort 3:In subjects with hormone receptor-positive HER2-low metastatic BC (Cohort 3): − Has recurrent disease <2 years from the initiation of adjuvant endocrine therapy (ET) OR − Has disease progression on CDK4/6 inhibitor-based regimen within 12 months of completion of adjuvant therapy with a CDK4/6 inhibitor OR - Has disease progression within the first 12 months of CDK4/6 in the first line metastatic setting.
6. - Presence of at least one measurable lesion based on computed tomography (CT) or magnetic resonance imaging (MRI) as assessed by the investigator, per RECIST v1.1 OR - At least 1 lesion, not previously irradiated, that can be measured accurately at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with CT or MRI which is suitable for accurate repeated measurements, or non-measurable, bone-only disease that can be assessed by CT or MRI or X-Ray. Lytic or mixed lytic bone lesions that can be assessed by CT or MRI or X-Ray in the absence of measurable disease as defined above is acceptable; subjects with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible.
7. Subjects with brain metastases are allowed in the study. The brain lesion(s) should be small (< 2 cm), untreated, asymptomatic, not requiring urgent medical intervention, and/or are asymptomatic and clinically stable.
8. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
9. Has a minimum life expectancy of 12 weeks at Screening.
10. Has a left ventricular ejection fraction (LVEF) ≥ 50% within 28 days before enrollment.
11. Has adequate organ and bone marrow function within 7 days before enrollment. Transfusion (red blood cell or platelet) or granulocyte-colony stimulating factor (G-CSF) administration is not allowed within 2 weeks prior to Screening assessment. Organ and bone marrow function criteria must also be met when laboratory tests are repeated within 3 days before dosing as appropriate. Adequate organ/bone marrow function are defined in the protocol.
12. Has adequate treatment washout period before enrollment, as defined in protocol.
13. A male participant capable of producing sperm is eligible to participate if he agrees to avoid donating sperm or to adhere to contraception methods as defined in the protocol, for at least the time needed to eliminate the trial intervention. The length of time required to continue contraception after last dose for the trial intervention is 4 months.
14. A female POCBP is eligible to participate if the following conditions are met: a. Participant is not pregnant as confirmed by highly sensitive pregnancy test. b. Participant does not breastfeed during the trial intervention period, and for at least 7 months after last dose of trial intervention. c. Participant agrees to adhere to a contraceptive method that is highly effective and agrees not to donate eggs (ova, oocytes) to others or freeze/store eggs during the intervention period and for at least the time needed to eliminate the trial intervention after the last dose. The length of time required to continue contraception after last dose for the trial intervention is 7 months. Preservation of eggs may be considered prior to first dose of trial intervention.
15. Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.

Exclusion criteria 21

1. Prior treatment with an ADC that consists of an exatecan derivative that is a topoisomerase I inhibitor (other than sacituzumab govitecan) including prior participation in a study involving an ADC produced by Daiichi Sankyo and/or AstraZeneca.
2. Uncontrolled or significant cardiovascular disease including any of the following: a. Subjects with a medical history of myocardial infarction within 6 months before randomization or symptomatic CHF (NYHA Class II to IV). Subjects 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 randomization to rule out myocardial infarction. b. Uncontrolled and/or clinically important cardiac arrhythmias.
3. Has a corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (males) based on average of the Screening triplicate 12-lead electrocardiogram (ECG).
4. Has a history of (non-infectious) 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.
5. Has spinal cord compression or clinically active central nervous system metastases, defined as 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.
6. Has primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, other solid tumours curatively treated, or contralateral BC.
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 systemic antibiotics, antivirals, or antifungals.
10. Has active or uncontrolled hepatitis B virus (HBV) infection. Hepatitis B screening tests are not required, unless there is a known history of HBV infection or if mandated by local health authority. Participants are eligible if they fulfil the conditions as described in the study protocol.
11. Has active or uncontrolled hepatitis C virus (HCV) infection. Hepatitis C screening tests are not required unless there is a known history of HCV infection or if mandated by local health authority. Participants are eligible if they meet the criteria as described in the study protocol.
12. Has active or uncontrolled human immunodeficiency virus (HIV) infection. Subjects must be tested for HIV viral load during the Screening Period if acceptable by local regulations or institutional review boards/independent ethics committees. Participants are eligible if they meet the criteria as described in the study protocol.
13. Has history of receiving a live, attenuated vaccine (messenger RNA and replication-deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first exposure to study drug.
14. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤1 or baseline. Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to Grade > 2 for at least 3 months prior to enrollment and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy including the following: a. Chemotherapy-induced neuropathy b. Fatigue c. Residual toxicities from prior immune-oncology (IO) treatment: Grade 1 or Grade 2 endocrinopathies, which may include the following: Hypothyroidism/hyperthyroidism; Type 1 diabetes; Hyperglycemia; Adrenal insufficiency; Adrenalitis; Skin hypopigmentation (vitiligo).
15. Is pregnant or breastfeeding or planning to become pregnant.
16. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the study randomisation, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, and pleural effusion, etc).
17. Any autoimmune, connective tissue or inflammatory disorders (eg, rheumatoid arthritis, Sjogren’s, sarcoidosis, etc) where there is documented or a suspicion of pulmonary involvement at the time of Screening. Full details of the disorder should be recorded in the electronic case report form (eCRF) for subjects who are included in the study.
18. Prior complete pneumonectomy.
19. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including ongoing or active infection, uncontrolled hypertension, renal transplant, active bleeding diseases, or serious chronic gastrointestinal conditions associated with diarrhea) substantially increasing risk of incurring AEs, which, in the investigator’s opinion, makes it undesirable for the subject to participate in the study or would jeopardize compliance with the protocol.
20. Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject’s participation in the clinical study or evaluation of the clinical study results.
21. Social, familial, or geographical factors that would interfere with study participation or follow-up.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary efficacy endpoint is Time to Next Treatment - TTNT. Subjects who did not receive any subsequent therapy and are alive at the time of analysis will be censored at the last contact date. In addition to the final analysis, an interim analysis will be performed when 60% of subjects in each cohort have experienced the primary endpoint, TTNT.

Secondary endpoints 5

1. Real-world PFS (rwPFS) (Progression-free survival), the key secondary endpoint, is defined as the time from the date of first administration of T-DXd to the date of first observed disease progression or death due to any cause. Disease progression will be determined by investigator assessment of tumor scans and using RECIST version 1.1 criteria.
2. Time to treatment discontinuation - TTD is defined as the time interval from the date of first dose of T-DXd to the date of discontinuation of T-DXd or death due to any cause. Subjects who do not discontinue treatment and are alive at the time of the analysis will be censored at their last contact date.
3. A TEAE (treatment-emergent adverse event) is defined as an AE that occurs, having been absent before the first dose of study drug, or has worsened in severity or seriousness after initiating the study drug until 47 days after the last dose of the study drug.
4. The PRO (Patient-reported Outcomes) analyses include the following: • Subjects with changed status (improvement or deterioration) in EORTC questionnaire scales • Time to first and definitive deterioration from baseline in EORTC questionnaire scales • Responses by level of severity from the EQ-5D-5L items • Scores of EORTC questionnaires, EQ-5D-5L index score, and VAS over time and change from baseline • Subjects within each response category for PGI-C, PGI-S, and PGITT
5. Overall response rate / objective response rate - ORR is defined as the proportion of subjects with a BOR of confirmed CR or confirmed PR according to the investigator and per RECIST version 1.1 criteria.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Daiichi Sankyo Inc.

Sponsor organisation

Daiichi Sankyo Inc.

Address

211 Mount Airy Road

City

Basking Ridge

Postcode

07920-2311

Country

United States

Scientific contact point

Organisation

Daiichi Sankyo Inc.

Contact name

Clinical Trial Office

Public contact point

Organisation

Daiichi Sankyo Inc.

Contact name

Clinical Trial Office

Third parties 6

Locations

6 EU/EEA countries · 51 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 130 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications