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HER2-positive Breast CancerPhase 2NCT05710666

Neoadjuvant Trastuzumab Deruxtecan (T-DXd) With Response-directed Definitive Therapy in Early Stage HER2-positive Breast Cancer (SHAMROCK Study)

A Phase 2 study testing trastuzumab deruxtecan (T-DXd) (IV) in people with HER2-positive Breast Cancer, run by Cancer Trials Ireland at 5 sites in Ireland.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

This study is a Phase 2 open label, single arm, adaptive multi-centre trial. Patients with early stage HER2-positive breast cancer will receive neoadjuvant treatment of trastuzumab deruxtecan (T-DXd) 5.4mg/kg intravenously every three weeks for up to six cycles. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
HER2-positive Breast Cancer
What is being tested?
trastuzumab deruxtecan (T-DXd) (IV)
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
11 participants
Where
5 sitesIreland
Study dates
26 Oct 2023to 30 Mar 2028
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Adult women and men ≥ 18 years of age.
  • Histologically confirmed HER2-positive breast cancer:
  • o Documented HER2 overexpression by local laboratory (IHC 3+ or FISH or CISH positive on diagnostic breast biopsy).
  • Newly diagnosed breast cancer, planned for neoadjuvant therapy prior to surgery.
  • Stages 2-3 breast cancer.
  • Patients should not have received any prior therapy for breast cancer.
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  • Patients must be willing to undergo mandatory tumour biopsy at Cycle 2 Day 14 (+/- 4 days) and (if applicable, refer to section 9.5 Tomosynthesis-Guided Core Biopsies sub-study and Table 8-2) before surgery .
  • ECOG performance status 0-1.
  • Availability of archival tumour biopsy tissue at screening.
  • Left ventricular ejection fraction (LVEF) ≥ 50%, as determined by ECHO or MUGA.
  • 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:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (granulocyte-colony stimulating factor administration is not allowed within 1 week prior to C1D1)
  • Platelet count ≥ 100 x 109/L (Platelet transfusion is not allowed within 1 week prior to C1D1)
  • 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).
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN)
  • Total bilirubin ≤ 1.5xULN or < 3×ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia)
  • Serum albumin ≥ 25 g/L
  • Creatinine clearance (CrCL) ≥ 30ml/min as determined by Cockcroft Gault (using actual body weight) (refer to Appendix C).
  • Prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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:
  • Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal).
  • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable and implantable).
  • Intrauterine device (IUD). iv. Intrauterine hormone-releasing system (IUS). v. Bilateral tubal occlusion. vi. Successfully vasectomised partner. vii. Sexual abstinence.
  • 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.
  • 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.

Who cannot join

  • Known metastatic or stage 4 breast cancer.
  • 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.
  • Corrected QT interval (QTcF) prolongation to >470 msec (females) or >450 msec (males) based on the screening 12-lead ECG.
  • Uncontrolled arterial hypertension despite optimal medical management (per investigator's opinion).
  • 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.
  • Non-healing wound, ulcer, or bone fracture.
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  • Active, clinically serious infections > CTCAE Grade 2 (CTCAE v5.0) requiring IV antibiotics, antivirals, or antifungals.
  • 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.
  • Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  • 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.
  • Lung criteria:
  • 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.)
  • 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.
  • Prior pneumonectomy (complete)
  • 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.
  • Pregnant or breast-feeding female patients, or patients who are planning to become pregnant.
  • Concomitant use of prohibited medications (refer to section 7.6.3: Prohibited Concomitant Medications and Treatments).
  • Known hypersensitivity to the test drug, test drug class, or excipients in the formulation.
  • History of severe hypersensitivity reactions to other monoclonal antibodies.
  • Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
  • Any illness or medical conditions that are unstable or could jeopardize the safety of patients and their compliance in the study.
  • Multiple primary malignancies within 3 years before study registration, with the exception of
  • adequately resected non-melanoma skin cancer
  • curatively treated in-situ disease
  • other solid tumours curatively treated

Trial locations and contacts

5 sites in 1 country.

5 sites in 1 country

Ireland5 sites

  • Cork University Hospital

    Cork, Munster

  • Saint Vincent's University Hospital

    Dublin, Leinster, D4

  • Beaumont Hospital

    Dublin, Leinster, D9

  • University Hospital Galway

    Galway, Connacht

  • University Hospital Limerick

    Limerick, Munster

Other trials in Ireland

About this study

Official title: 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

This study is a Phase 2 open label, single arm, adaptive multi-centre trial. Patients with early stage HER2-positive breast cancer will receive neoadjuvant treatment of trastuzumab deruxtecan (T-DXd) 5.4mg/kg intravenously every three weeks for up to six cycles.

Read the detailed description

In this single arm Phase 2 trial we will administer T-DXd 5.4mg/kg intravenously every three weeks for up to six cycles. A mandatory repeat biopsy at Cycle 2 Day 14 +/- 4 days of starting T-DXd will be performed for the RNA Disruption Index (RDI) score assessment. As a safety measure patients will undergo clinical examination before each cycle of T-DXd to enable early identification of on-treatment locoregional progression. If progression is seen then T-DXd will be stopped and the patient will be taken off study treatment. In the absence of early progression, those patients with a high chance of pathological complete response (pCR) based on the RDI score will undergo repeat breast imaging after four cycles of T-DXd. Patients who have a high chance of pCR based on the RDI score will proceed to surgery after four cycles of T-DXd if they also have imaging complete response (iCR) at that point. Other patients who have a high chance of pCR based on the RDI score but iCR is not attained after four cycles or who have a low/intermediate chance of pCR based on the RDI score will undergo repeat breast imaging after six cycles of T-DXd. Patients with iCR after six cycles of T-DXd regardless of RDI score will proceed to surgery. Patients who have a low/intermediate chance of pCR based on the RDI score and residual disease on imaging after six cycles of T-DXd will undergo either further systemic therapy or proceed to surgery (at the discretion of their treating physician).

Based on the surgical specimen, patients who achieve a pCR will undergo further trastuzumab post-operatively to complete a total of 52 weeks of systemic therapy from the first cycle of T-DXd. Patients with residual disease at surgery will receive adjuvant chemotherapy as decided by the treating physician.

Being tested
trastuzumab deruxtecan (T-DXd) (IV)

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • trastuzumab deruxtecan (T-DXd) (IV)Drug

    Administered as an intravenous (IV) infusion at a dose of 5.4 mg/kg on Day 1 of each 21-day cycle for up to six cycles.

Study groups in NCT05710666
Study groupRoleWhat they receive
T-DXdExperimentalNot described
Receives: Drug: trastuzumab deruxtecan (T-DXd) (IV)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. The percentage of patients who achieve pCR after T-DXd treatment

    The percentage of patients who achieve pCR after T-DXd treatment and thus avoid standard cytotoxic chemotherapy

    Measured: From registration until surgery, approximately 18 weeks

Secondary outcomes (14)

  1. pCR rate in all other patients (patients who could not avoid standard cytotoxic chemotherapy) and in the entire study population.

    Measured: From registration until surgery, approximately 18 weeks

  2. 3-year EFS of patients treated with only T-DXd and trastuzumab.

    EFS is defined as time from registration to disease recurrence, progression or death from any cause.

    Measured: 3 years from registration

  3. 3-year overall survival (OS) of patients treated with only T-DXd and trastuzumab.

    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.

    Measured: 3 years from registration

  4. 3-year EFS of patients treated with systemic therapy other than trastuzumab in addition to T-DXd.

    Measured: 3 years from registration

  5. 3-year OS of patients treated with systemic therapy other than trastuzumab in addition to T-DXd.

    Measured: 3 years from registration

  6. 3-year EFS and OS of the entire study population.

    Measured: 3 years from registration

  7. 3-year OS of the entire study population.

    Measured: 3 years from registration

  8. 3-year EFS difference between patients achieving vs not achieving pCR at surgery.

    Measured: 3 years from registration

  9. 3-year OS difference between patients achieving vs not achieving pCR at surgery.

    Measured: 3 years from registration

  10. Molecular evolution of tumours during treatment assessed by ctDNA.

    Measured: From registration until end of study treatment, approximately 23 weeks

  11. Molecular evolution of tumours during treatment assessed by protein biomarkers.

    Measured: From registration until end of study treatment, approximately 23 weeks

  12. Molecular evolution of tumours during treatment assessed by CTCs analysis.

    Measured: From registration until end of study treatment, approximately 23 weeks

  13. Percentage of patients who achieve pCR after 4 cycles of T-DXd.

    Measured: From registration until surgery, approximately 18 weeks

  14. The sensitivity and specificity for prediction of pCR of RDI and imaging and tomosynthesis biopsy alone and in combination.

    Measured: From registration until surgery, approximately 18 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Feb 2023
  2. Study start26 Oct 2023
  3. Primary completion30 Sep 2025 (estimated)
  4. Study completion30 Mar 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
11 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05710666
Sponsor's protocol ID
CTRIAL-IE 22-01
Other IDs
2022-002485-32
Status last verified
Aug 2024
First submitted
20 Dec 2022
Last updated
5 Aug 2024
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Dowling GP, Toomey S, Bredin P, Parker I, Mulroe E, Marron J, McLoughlin O, Teiserskiene A, Power C, O'Shea AM, Greally M, Morris PG, Duke D, Hill ADK, Hennessy BT. Neoadjuvant trastuzumab deruxtecan (T-DXd) with response-directed definitive therapy in early stage HER2-positive breast cancer: a phase II study protocol (SHAMROCK study). BMC Cancer. 2024 Jan 17;24(1):91. doi: 10.1186/s12885-024-11851-4.

    PubMed 38233810

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing trastuzumab deruxtecan (T-DXd) (IV) in people with HER2-positive Breast Cancer, run by Cancer Trials Ireland at 5 sites in Ireland.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 30 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 5 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in Ireland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The percentage of patients who achieve pCR after T-DXd treatment (time frame: From registration until surgery, approximately 18 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05710666, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Aug 2024.

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