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
- Phase
- Phase 2
- Intervention
- trastuzumab deruxtecan (T-DXd) (IV)
- Conditions
- HER2-positive Breast Cancer
- Sponsor
- Cancer Trials Ireland
- Enrollment
- 11
- Locations
- 5
- Primary Endpoint
- The percentage of patients who achieve pCR after T-DXd treatment
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief 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.
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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.
- •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-
- •Availability of archival tumour biopsy tissue at screening.
- •Left ventricular ejection fraction (LVEF) ≥ 50%, as determined by ECHO or MUGA.
Exclusion Criteria
- •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.
- •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.
Arms & Interventions
T-DXd
Intervention: trastuzumab deruxtecan (T-DXd) (IV)
Outcomes
Primary Outcomes
The percentage of patients who achieve pCR after T-DXd treatment
Time Frame: From registration until surgery, approximately 18 weeks
The percentage of patients who achieve pCR after T-DXd treatment and thus avoid standard cytotoxic chemotherapy
Secondary Outcomes
- 3-year OS of patients treated with systemic therapy other than trastuzumab in addition to T-DXd.(3 years from registration)
- 3-year overall survival (OS) of patients treated with only T-DXd and trastuzumab.(3 years from registration)
- 3-year OS of the entire study population.(3 years from registration)
- Percentage of patients who achieve pCR after 4 cycles of T-DXd.(From registration until surgery, approximately 18 weeks)
- 3-year EFS of patients treated with only T-DXd and trastuzumab.(3 years from registration)
- Molecular evolution of tumours during treatment assessed by ctDNA.(From registration until end of study treatment, approximately 23 weeks)
- Molecular evolution of tumours during treatment assessed by CTCs analysis.(From registration until end of study treatment, approximately 23 weeks)
- The sensitivity and specificity for prediction of pCR of RDI and imaging and tomosynthesis biopsy alone and in combination.(From registration until surgery, approximately 18 weeks)
- pCR rate in all other patients (patients who could not avoid standard cytotoxic chemotherapy) and in the entire study population.(From registration until surgery, approximately 18 weeks)
- 3-year EFS of patients treated with systemic therapy other than trastuzumab in addition to T-DXd.(3 years from registration)
- 3-year EFS and OS of the entire study population.(3 years from registration)
- Molecular evolution of tumours during treatment assessed by protein biomarkers.(From registration until end of study treatment, approximately 23 weeks)
- 3-year EFS difference between patients achieving vs not achieving pCR at surgery.(3 years from registration)
- 3-year OS difference between patients achieving vs not achieving pCR at surgery.(3 years from registration)