Trial Title:
NeoAdjuvant Therapy With Trastuzumab-deruxtecan Versus Chemotherapy+Trastuzumab+Pertuzumab in HER2+ Early Breast Cancer
NCT ID:
NCT05704829
Condition:
HER2-positive Early Breast Cancer
Conditions: Official terms:
Breast Neoplasms
Trastuzumab
Trastuzumab deruxtecan
Conditions: Keywords:
HER2+
T-DXd
Trastuzumab-deruxtecan
pCR
intermediate risk
high risk
low risk
recurrence
neoadjuvant
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Crossover Assignment
Intervention model description:
This is a multicentre, interventional, prospective, two-arm, randomised, open-label,
controlled (neo-)adjuvant, phase-II trial evaluating the efficacy and safety of
trastuzumab-deruxtecan (T-DXd) vs. standard-of-care paclitaxel + trastuzumab + pertuzumab
(PAC+T+P) in low- to intermediate-risk or docetaxel/paclitaxel + carboplatin +
trastuzumab + pertuzumab in intermediate- to high-risk HER2+ early breast cancer in pre-
and postmenopausal women.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Trastuzumab deruxtecan
Description:
T-DXd i.v.
Arm group label:
T-DXd: HER2+ and intermediate-high risk for recurrence
Arm group label:
T-DXd: HER2+ and low-intermediate risk for recurrence
Other name:
ENHERTU
Intervention type:
Drug
Intervention name:
Standard-of-Care
Description:
Chemotherapy+T+P
Arm group label:
Control: HER2+ and intermediate-high risk for recurrence
Arm group label:
Control: HER2+ and low-intermediate risk for recurrence
Other name:
Chemotherapy+T+P
Summary:
ADAPT-HER2-IV will address question of optimal neoadjuvant therapy in patients with less
advanced -HER2+ EBC.
ADAPT-HER2-IV is planned as a superiority trial to demonstrate higher pCR rates in both
clinically relevant subgroups of low-intermediate risk HER2+ EBC. Moreover, it aims to
demonstrate excellent survival in patients treated by T-DXd (with the use of standard
chemotherapy at investigator´s decision restricted only to patients with substantial
residual tumour burden after T-DXd-treatment).
Detailed description:
As the ADAPT-trials have clearly shown, pCR after 12 weeks of therapy, independent of the
specific de-escalated neoadjuvant regimen and independent of further use of systemic
chemotherapy, is an independent predictor of excellent prognosis4,19, also in patients
treated by an antibody-drug conjugate alone (T-DM1), or in those receiving
pertuzumab+trastuzumab+/-weekly paclitaxel.
In contrast to the adjuvant setting, none of the neoadjuvant trials so far has focused on
HER2+ patients with a low-intermediate risk profile (e.g., node-negative patients with
cT1-2 tumours). The ADAPT-HER2-IV trial aims to close this evidence gap.
Since there is some uncertainty about the optimal treatment duration in intermediate- to
high-risk HER2+ EBC (e.g., tumour size >3 cm), we recommend using a longer 18-week
taxane-based treatment (+/- carboplatin, at investigator´s decision) due to a large body
of evidence for taxane + carboplatin combinations in patients in locally advanced stages.
Antibody-drug conjugates appear to be ideal candidate drugs for a "de-escalated"
treatment due to their favourable safety (reduced alopecia, polyneuropathy rates, etc.)
and a high efficacy profile (e.g., comparable pCR rates after 18 weeks of T-DM1 and
taxane+pertuzumab+trastuzumab in the PREDIX HER2 trial20). Similarly to the classical
chemotherapy landscape, optimal duration of antibody-drug conjugate-based neoadjuvant
therapy remains unclear. pCR rates of around 40% to 60% were observed after 12 and 18
weeks of T-DM1 treatment (+/-pertuzumab) in the ADAPT TP, KRISTINE and PREDIX HER2 trials
in HR+/HER2+ disease21,22. Moreover, long-term survival seem to be comparable between
T-DM1+pertuzumab and older chemotherapy-containing regimens
(docetaxel+carboplatin+trastuzumab+pertuzumab) despite of higher local progression rates
and lower pCR in one study22.
Trastuzumab-deruxtecan (T-DXd) has shown promising activity in a small cohort of
metastatic patients, including both HER2+ and HER2-low BC, pre-treated with several lines
of therapy. Doi et al. reported overall response rates (ORR) of 58% and a disease control
rate of 100% with overall survival at 12 months at in HER2+ disease pre-treated by
T-DM1+/-pertuzumab in a late line setting23. T-DXd-therapy was associated with a
manageable safety profile. Recently, clearly higher efficacy of T-DXd vs. T-DM1 was shown
in second line metastatic breast cancer (MBC) in the DESTINY-03 trial24. Median
progression free survival was not reached in T-DM1-arm vs. 6.8 months in the T-DXd-arm.
This effect was independent of hormone receptor status, prior pertuzumab treatment,
visceral metastases, number of prior therapy lines and presence of brain metastases. ORR
was doubled (34.2 vs. 79.7%), favouring the T-DXd arm.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
Patients eligible for inclusion in this study must meet all the following criteria:
1. Female patients with invasive, untreated HER2+ breast cancer (as assessed by local
pathology) maximum 6 weeks before registration (standard-of-care diagnostic biopsy
according to current AGO guidelines)
2. Age ≥18 years 3a. Cohort 1: low- to intermediate-risk for recurrence as per
investigator´s decision (recommendation: cT1c - cT2 (1 - ≤3cm), cN0; cT1a/b
excluded), OR 3b. Cohort 2: intermediate- to high-risk for recurrence as per
investigator´s decision (recommendation: cT2 (>3 - ≤5cm), cN0) 3c. Elderly patients
(≥ 65 years) may be assigned to any cohort as per investigator's decision
4. Written informed consent 5. LVEF ≥ 50% within 28 days before randomisation 6.
Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 7. Adequate
organ and bone marrow function within 14 days before randomisation 8. Adequate
treatment washout period before randomisation (refer to protocol for detailed
information) 9. Evidence of post-menopausal status or negative serum pregnancy test
for females of childbearing potential (refer to protocol for detailed information)
10. Female subjects must not donate, or retrieve for their own use, ova from the
time of randomisation and throughout the study treatment period, and for at least 7
months after the final study drug administration. (refer to protocol for detailed
information)
Exclusion Criteria:
Patients eligible for inclusion in this study must not meet any of the following
criteria:
1. Non-operable breast cancer including inflammatory breast cancer
2. cT1a/b breast cancer
3. Any previous history of invasive breast cancer
4. Primary malignancies within 5 years, with the exception of adequately resected
non-melanoma skin cancer, curatively treated in-situ disease
5. Any evidence for existing metastatic disease (confirmed by CT Thorax/Abdomen, bone
scan, or other methods according to clinical practice
6. Previous or concurrent treatment with cytotoxic agents for any reason (except
non-oncological reasons)
7. Concurrent treatment with other experimental drugs and participation in another
clinical trial with any investigational drug within 30 days prior to study entry
8. Severe and relevant co-morbidity that would interact with the application of
cytotoxic agents or the participation in the study/inadequate organ function
9. Reasons indicating risk of poor compliance
10. Woman of child-bearing potential defined as a woman physiologically capable of
becoming pregnant, and not using highly effective methods of contraception during
the study treatment and for 3 months after stopping the treatment.
11. Use of oral (oestrogen and progesterone), transdermal, injected, or implanted
hormonal methods of contraception as well as hormonal replacement therapy.
12. Has substance abuse or any other medical conditions such as clinically significant
cardiac or psychological conditions, that may, in the opinion of the investigator,
interfere with the subject's participation in the clinical study or evaluation of
the clinical study results.
13. Patients with a medical history of myocardial infarction (MI) within 6 months before
randomisation, symptomatic congestive heart failure (CHF) (New York Heart
Association Class II to IV), Subjects with troponin levels above ULN at screening
(as defined by the manufacturer), and without any myocardial related symptoms,
should have a cardiologic consultation before enrolment to rule out MI.
14. Corrected QT interval (QTcF) prolongation to > 470 msec (females) based on average
of the screening triplicate12-lead ECG.
15. 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.
16. Lung criteria: Lung-specific intercurrent clinically significant illnesses
including, but not limited to, any underlying pulmonary disorder; 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 randomisation; Prior pneumonectomy (complete); Uncontrolled infection
requiring IV antibiotics, antivirals, or antifungals
17. 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.
Patients should be tested for HIV prior to randomisation if required by local
regulations or ethics committee (EC).
18. 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.
19. Known allergy or hypersensitivity to study treatment (T-DXd) or any of the study
drug excipients.
20. History of severe hypersensitivity reactions to other monoclonal antibodies.
21. Pregnant or breastfeeding female patients, or patients who are planning to become
pregnant.
Gender:
Female
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Breast Center of the University of Munich (LMU) Universitätsfrauenklinik
Address:
City:
Munich
Zip:
81377
Country:
Germany
Facility:
Name:
Rotkreuz Klinikum München
Address:
City:
Muenchen
Zip:
80637
Country:
Germany
Facility:
Name:
Niels-Stensen-Kliniken Franziskus-Hospital
Address:
City:
Georgsmarienhütte
Zip:
49124
Country:
Germany
Facility:
Name:
Kliniken Essen-Mitte, Klinik für Senologie/Interdisziplinäres Brustzentrum
Address:
City:
Essen
Zip:
45136
Country:
Germany
Facility:
Name:
Brustzentrum Niederrhein, Johanniter Bethesda Krankenhaus
Address:
City:
Moenchengladbach
Zip:
41061
Country:
Germany
Facility:
Name:
Klinikum Mittelbaden, Brustzentrum
Address:
City:
Baden-Baden
Country:
Germany
Facility:
Name:
Onkologische Schwerpunktpraxis Bielefeld
Address:
City:
Bielefeld
Zip:
33604
Country:
Germany
Facility:
Name:
Universitätsklinikum Essen, Burstzentrum
Address:
City:
Essen
Country:
Germany
Facility:
Name:
Onkodok Gütersloh
Address:
City:
Gütersloh
Country:
Germany
Facility:
Name:
Brustzentrum am Krankenhaus Jerusalem
Address:
City:
Hamburg
Country:
Germany
Facility:
Name:
St. Barbara Klinik
Address:
City:
Hamm
Country:
Germany
Facility:
Name:
Helios-Klinik Wuppertal
Address:
City:
Wuppertal
Country:
Germany
Start date:
December 2023
Completion date:
June 2028
Lead sponsor:
Agency:
West German Study Group
Agency class:
Other
Collaborator:
Agency:
AstraZeneca
Agency class:
Industry
Source:
West German Study Group
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05704829
