DESTINY-Breast11 will compare trastuzumab deruxtecan (T-DXd) alone or in sequence with other medications, known as THP, with standard of care treatment (ddAC-THP) and determine its safety and efficacy in patients with HER2-positive early breast cancer.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Dec 2021 → ongoing

Decision date (initial)

2024-10-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

ASTRAZENECA AB

External identifiers

EU CT number

2023-505210-18-00

EudraCT number

2021-000603-21

ClinicalTrials.gov

NCT05113251

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacogenetic, Safety, Pharmacogenomic, Pharmacokinetic, Efficacy

"This is a Phase 3, open-label, three-arm study to determine the safety and efficacy of T-DXd monotherapy or T-DXd followed by THP as neoadjuvant treatment compared to standard of care (ddAC-THP) in participants with locally advanced or inflammatory HER2-positive early breast cancer.

The target population of interest in this study is participants with high-risk HER2-positive early breast cancer. Participants will be randomized in a 1:1:1 ratio to one of the following intervention groups: T DXd monotherapy (Arm A), T-DXd followed by THP (Arm B), or ddAC-THP (Arm C).

The primary objective is to demonstrate the superiority of neoadjuvant T-DXd alone or in sequence with THP relative to ddAC-THP by assessment of pCR (pathological complete response, ypT0/Tis ypN0) using central evaluation in participants with HER2-positive early breast cancer."

Secondary objectives 1

1. To assess the effectiveness of neoadjuvant T-DXd alone or in sequence with THP relative to ddAC-THP by assessment of a (i) secondary definition of pCR (ypT0 ypN0) using central evaluation, (ii) 3-year EFS (event-free survival), (iii) 3-year IDFS (invasive-disease free survival), and (iv) OS (overall survival). Data will also be collected to demonstrate the tolerability, safety, immunogenicity and PK of the investigational product.

Conditions and MedDRA coding

Early stage HER2-positive breast cancer (T stage >= T3, lymph node positive, or inflammatory)

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared. AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment https://vivli.org/. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Patients must be at least 18 years of age.
2. Histologically documented HER2-positive EBC participants with: (a) Locally assessed HER2-positive (IHC 3+ or ISH+) according to ASCO-CAP guidelines and prospectively centrally confirmed as HER2 positive based on a tumour sample (b) Unifocal and multifocal tumours (> 1 tumour confined to the same quadrant as the primary tumour) must have 1 focus sampled and centrally confirmed as HER2 positive (c) Multi-centric tumours (multiple tumours involving > 1 quadrant of the breast) must have 1 lesion from each involved quadrant sampled and centrally confirmed as HER2 positive. All quadrants tested must be centrally confirmed as HER2 positive (d) Tumours documented as HR-positive (either ER and/or PgR positive [ER or PgR ≥ 1%]) or HR-negative (ER and PgR negative) by local assessment per ASCO-CAP guidelines (Allison et al 2020) (e) Clinical stage at presentation (based on mammogram or breast MRI assessment): T0-4 (inclusive of inflammatory breast cancer), N1-3, M0 or ≥ T3, N0, M0 as determined by the AJCC staging system, 8th edition (Hortobagyi et al 2017) (f) Pathologic confirmation of nodal involvement with malignancy as determined by fine-needle aspiration or core-needle biopsy, when applicable.
3. FFPE tissue block (2 cores) or 20 freshly-cut, serial tumor slides for HER2 assessment by central lab. If blocks are incomplete or fewer than 20 slides are available, participants may be eligible following discussion with the AstraZeneca Study Physician​
4. ECOG performance status of 0 or 1 at randomization
5. Adequate organ and bone marrow function
6. LVEF ≥ 50% within 28 days before randomization

Exclusion criteria 12

1. Prior history of invasive breast cancer
2. Any primary malignancy within 3 years, except adequately resected non-melanoma skin cancer, or curatively treated in situ disease Note: This includes a second current breast primary malignancy (ie, bilateral breast cancer)
3. History of DCIS, except for participants treated with mastectomy only > 5 years prior to current diagnosis
4. Prior sentinel lymph node biopsy or axillary lymph node dissection before initiation of neoadjuvant treatment
5. Prior systemic therapy for the treatment of breast cancer
6. Previous treatment with anthracyclines, cyclophosphamide or taxanes for any malignancy; cyclophosphamide allowed for non-cancer treatment if last dose > 6 months
7. Ineligible for any medication in the control Arm C
8. Any concurrent anticancer treatment
9. History of non-infectious ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
10. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any pulmonary disorder
11. Investigator judgement of 1 or more of the following:​ (a) Mean resting corrected QTcF interval of >470 ms (females) or >450 ms (males)​ (b) History of QT prolongation associated with other medications that required discontinuation of that medication or any medication known to prolong QT interval and cause TdP.​ (c) Congenital long QT syndrome, family history of long QT syndrome or unexplained death under 40 years in first degree relatives
12. History of arrhythmia, symptomatic or uncontrolled atrial fibrillation or asymptomatic sustained ventricular tachycardia

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. pCR (ypT0/Tis ypN0): Rate of pCR is defined as the proportion of participants who have no evidence by H&E staining of residual invasive disease in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0) by central evaluation following completion of neoadjuvant therapy.

Secondary endpoints 8

1. pCR (ypT0 ypN0): Rate of pCR is defined as the proportion of participants who have no evidence by H&E staining of residual invasive disease and in situ cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0 ypN0) following completion of neoadjuvant therapy.
2. EFS
3. IDFS
4. OS
5. HRQoL: Symptomatic AEs assessed by the PRO-CTCAE and items from the EORTC Item Library. Overall side-effect bother measured by PGI-TT at each time point in each treatment arm. Physical function assessed by the EORTC QLQ-C30 Physical Function Scale.
6. Safety and Tolerability: Occurrence of AEs, SAEs and changes from baseline in vital signs, clinical laboratory results, ECGs, and ECHO/MUGA. Heart failure evaluated by the percentage of participants with NYHA Class III and IV heart failure. Decreases in LVEF (requires at least 2 consecutive readings of decline) by percentage of participants with decreases in LVEF of at least 10 points from baseline and to below 50%.
7. PK of T-DXd: Serum concentration of T-DXd, anti-HER2 antibody, and DXd.
8. Immunogenicity for T-DXd: Number and percentage of participants who develop ADAs for T-DXd.

Investigational products

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

Test 5

Comparator 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

Clinical Study Information Center

Locations

4 EU/EEA countries · 33 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 30 files

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

Application history

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