Single arm phase 2 trial of neoadjuvant trastuzumab deruxtecan (T-DXd) with response-directed definitive therapy in early stage HER2-positive breast cancer: a standard chemotherapy-sparing approach to curative-intent treatment – SHAMROCK study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Cancer Trials Ireland

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

1 May 2026 → ongoing

Decision date (initial)

2024-09-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-516582-36-00

EudraCT number

2022-002485-32

ClinicalTrials.gov

NCT05710666

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenomic, Efficacy, Safety, Therapy

To evaluate the efficacy of T-DXd in the neo-adjuvant treatment of HER2 positive breast cancer using imaging complete response (iCR) after 4 cycles of treatment as the primary endpoint.

Secondary objectives 15

1. To determine the Event-free survival (EFS) and overall survival (OS) of patients treated with only T-DXd and adjuvant trastuzumab.
2. To determine EFS and OS of patients treated with systemic therapy other than adjuvant trastuzumab in addition to T-DXd.
3. To determine EFS and OS of the entire study population.
4. To compare EFS and OS between patients achieving vs not achieving pCR at surgery.
5. To compare EFS and OS by RDI zone.
6. To determine the percentage of patients who achieve iCR after 4 cycles of T-DXd by RDI zone.
7. To determine the overall percentage of patients who achieve iCR after any study treatment (i.e. either after 4 or 8 cycles of study treatment) and by RDI zone.
8. To determine the percentage of patients who achieve pCR after 4 cycles of T-DXd and by RDI zone (high vs low/intermediate score).
9. To determine the overall percentage of patients who achieve pCR at surgery (i.e. either after 4 or 8 cycles of study treatment) and by RDI zone.
10. To study molecular evolution of tumours during treatment and to develop a biomarker panel that optimises prediction of the pCR.
11. To explore the performance metrics (Negative Predictive Value (NPV), Positive Predictive Value (PPV), sensitivity, specificity) for prediction of non-pCR /pCR of RDI alone, imaging alone, and the combination of RDI with imaging.
12. To assess safety and tolerability of study treatment T-DXd, and THP.
13. To assess the composition of the gut microbiome (GM) before and after neoadjuvant treatment and to examine any association between the GM and the pathological response at the time of surgery.
14. To investigate the utility of Tumour-Infiltrating Lymphocytes (TILs) as a biomarker of response to T-DXd in early stage HER2-positive breast cancer.
15. To investigate the utility of lung specific DNA markers in breath for prediction of the occurrence of pneumonitis.

Conditions and MedDRA coding

Early stage HER2-positive breast cancer

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Adult women and men ≥ 18 years of age.
2. Histologically confirmed HER2-positive breast cancer: o Documented HER2 overexpression by local laboratory (IHC 3+ or positive by ISH on diagnostic breast biopsy (as defined in 2018 American Society of Clinical Oncology – College of American Pathologists [ASCO-CAP] guidelines)).
3. Newly diagnosed breast cancer, planned for neoadjuvant therapy prior to surgery.
4. Stages 2-3 breast cancer.
5. Patients should not have received any prior therapy for breast cancer.
6. Patients must be willing to undergo mandatory tumour biopsy at Cycle 2 Day 14 (+/- 4 days) and (if applicable) at Cycle 5 Day 14-21.
7. ECOG performance status 0-1.
8. Availability of archival tumour biopsy tissue at screening.
9. Left ventricular ejection fraction (LVEF) ≥ 50%, as determined by ECHO or MUGA.
10. Adequate laboratory values collected no more than 14 days before registration. All parameters must meet the inclusion criteria on the same day, and must be the most recent results available: o Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (granulocyte-colony stimulating factor administration is not allowed within 1 week prior to C1D1) o Platelet count ≥ 100 x 109/L (Platelet transfusion is not allowed within 1 week prior to C1D1) o Haemoglobin ≥ 9.0 g/dL. NOTE: Participants requiring ongoing transfusions or growth factor support to maintain haemoglobin ≥9.0 g/dL are not eligible (Red blood cell transfusion is not allowed within 1 week prior to C1D1). o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN) o Total bilirubin ≤ 1.5xULN or < 3×ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) o Serum albumin ≥ 25 g/L o Creatinine clearance (CrCL) ≥ 30ml/min as determined by Cockcroft Gault (using actual body weight) (refer to Appendix C). o Prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN.
11. Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test must be available at the screening visit. Women of childbearing potential are defined as those who are not surgically sterile (i.e. underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Postmenopausal women defined as: i. Women aged <50 years will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the site. ii. Women aged ≥50 years will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments. iii. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for women of child-bearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to registration. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
12. Women of childbearing potential must agree to use a highly effective method of contraception according to current HMA CTFG guideline when sexually active. This applies from signing of the informed consent form until at least 7 months after the last IMP administration. The investigator or a designated associate is required to advise the patient how to achieve an adequate birth control. Highly effective contraception is defined in the study as methods that achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods include: i. Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal). ii. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable and implantable). iii. Intrauterine device (IUD). iv. Intrauterine hormone-releasing system (IUS). v. Bilateral tubal occlusion. vi. Successfully vasectomised partner. vii. Sexual abstinence.
13. Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose of IMP. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is in line with the patient’s usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. It is strongly recommended for the female partners of a male patient to also use at least one highly effective method of contraception throughout this period. In addition, male patients should refrain from fathering a child, or freezing or donating sperm from the time of registration, throughout the study and for 4 months after the last dose of IMP. Preservation of sperm should be considered prior to enrollment in this study.
14. Female patients must not donate, or retrieve for their own use, ova from the time of registration and throughout the study treatment period, and for at least 7 months after the final IMP administration. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrollment in this study.

Exclusion criteria 19

1. Known metastatic or stage 4 breast cancer.
2. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction (MI) less than 6 months before registration, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV). Patients with troponin levels above ULN at screening and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out MI.
3. Corrected QT interval (QTcF) prolongation to >470 msec (females) or >450 msec (males) based on the screening 12-lead ECG.
4. Uncontrolled arterial hypertension despite optimal medical management (per investigator’s opinion).
5. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before registration.
6. Non-healing wound, ulcer, or bone fracture.
7. Active, clinically serious infections > CTCAE Grade 2 (CTCAE v5.0) requiring IV antibiotics, antivirals, or antifungals.
8. Patients with evidence or history of bleeding diathesis. Any haemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study treatment.
9. Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, or active hepatitis B (HBV) or C (HCV) infection. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients with current active or history of hepatitis B infection with either HBsAg(+) or anti-HBc(+) are not eligible.
10. 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.
11. Lung criteria: a. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within three months before study registration, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc.) b. Any autoimmune, connective tissue or inflammatory disorders (e.g. 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 eCRF for patients who are included in the study. c. Prior pneumonectomy (complete)
12. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of trastuzumab deruxtecan. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IMP.
13. Pregnant or breast-feeding female patients, or patients who are planning to become pregnant.
14. Concomitant use of prohibited medications (refer to section 7.6.3: Prohibited Concomitant Medications and Treatments).
15. Known hypersensitivity to the test drug, test drug class, or excipients in the formulation.
16. History of severe hypersensitivity reactions to other monoclonal antibodies.
17. Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.
18. Any illness or medical conditions that are unstable or could jeopardize the safety of patients and their compliance in the study.
19. Multiple primary malignancies within 3 years before study registration, with the exception of a. adequately resected non-melanoma skin cancer b. curatively treated in-situ disease c. other solid tumours curatively treated

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The percentage of patients who achieve iCR after 4 cycles of T-DXd treatment and thus avoid standard cytotoxic chemotherapy. Imaging complete response (iCR) is defined as the resolution of all previously described suspicious abnormalities.

Secondary endpoints 15

1. 3-year EFS and OS of patients treated with only T-DXd and adjuvant trastuzumab. EFS is defined as time from registration to disease recurrence, progression, or death from any cause. OS is defined as the time from registration to date of death from any cause, censored at date last known to be alive for those who have not died.
2. 3-year EFS and OS of patients treated with systemic therapy other than adjuvant trastuzumab in addition to T-DXd.
3. 3-year EFS and OS of the entire study population.
4. 3-year EFS and OS difference between patients achieving vs not achieving pCR at surgery.
5. 3-year EFS and OS difference between patients with high RDI Score vs low/intermediate score.
6. Percentage of patients who achieve iCR after only 4 cycles of T-DXd by RDI Zone (high vs low/intermediate score).
7. Overall percentage of patients who achieve iCR after any treatment (i.e. either after 4 or 8 cycles of treatment) and by RDI Zone (high vs low/intermediate score).
8. Percentage of patients who achieve pCR at surgery after 4 cycles of T-DXd and by RDI Score (high vs low/intermediate score).
9. Overall percentage of patients who achieve pCR at surgery (i.e. either after 4 or 8 cycles of treatment) and by RDI Zone (high vs low/intermediate score).
10. Molecular evolution of tumours during treatment.
11. The performance metrics (NPV, PPV, sensitivity, specificity) for prediction of non-pCR / pCR of RDI alone, imaging alone and combination of RDI with imaging
12. To evaluate the safety and tolerability of study treatment T-DXd, and THP as measured by incidence of adverse events reported and toxicity evaluation as per the NCI Common Terminology Criteria for Adverse Events (CTCAE version 5.0).
13. The composition of the gut microbiome (GM) before and after neoadjuvant treatment and any association between the GM and the pathological response at the time of surgery.
14. The utility of Tumour-Infiltrating Lymphocytes (TILs) as a biomarker of response to T-DXd in early stage HER2-positive breast cancer
15. The utility of lung specific DNA markers in breath for prediction of the occurrence of pneumonitis.

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Cancer Trials Ireland

Sponsor organisation

Cancer Trials Ireland

Address

Rcsi House, 121 Saint Stephen's Green 121 Saint Stephen's Green

City

Dublin 2

Postcode

D02 H903

Country

Ireland

Scientific contact point

Organisation

Cancer Trials Ireland

Contact name

Head of Operations

Public contact point

Organisation

Cancer Trials Ireland

Contact name

Head of Operations

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Temporary halts 2 · Art. 38 CTR

Results and documents

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

Documents 10 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