Trial Title:
Neoadjuvant Trastuzumab Deruxtecan (T-DXd) With Response-directed Definitive Therapy in Early Stage HER2-positive Breast Cancer (SHAMROCK Study)
NCT ID:
NCT05710666
Condition:
HER2-positive Breast Cancer
Conditions: Official terms:
Breast Neoplasms
Trastuzumab
Trastuzumab deruxtecan
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Active, not recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
trastuzumab deruxtecan (T-DXd) (IV)
Description:
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.
Arm group label:
T-DXd
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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
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 FISH or CISH
positive on diagnostic breast biopsy).
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, refer to section 9.5 Tomosynthesis-Guided Core Biopsies
sub-study and Table 8-2) before surgery .
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:
- 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.
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:
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 or C infection. Patients positive for hepatitis C (HCV)
antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
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:
1. 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.)
2. 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.
3. 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
1. adequately resected non-melanoma skin cancer
2. curatively treated in-situ disease
3. other solid tumours curatively treated
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
University Hospital Galway
Address:
City:
Galway
Country:
Ireland
Facility:
Name:
Saint Vincent's University Hospital
Address:
City:
Dublin
Zip:
D4
Country:
Ireland
Facility:
Name:
Beaumont Hospital
Address:
City:
Dublin
Zip:
D9
Country:
Ireland
Facility:
Name:
Cork University Hospital
Address:
City:
Cork
Country:
Ireland
Facility:
Name:
University Hospital Limerick
Address:
City:
Limerick
Country:
Ireland
Start date:
October 26, 2023
Completion date:
March 30, 2028
Lead sponsor:
Agency:
Cancer Trials Ireland
Agency class:
Other
Source:
Cancer Trials Ireland
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05710666
