Clinical trial NCT05704829: NeoAdjuvant Therapy With Trastuzumab-deruxtecan Versus Chemotherapy+Trastuzumab+Pertuzumab in HER2+ Early Breast Cancer
Official title: NeoAdjuvant Dynamic Marker - Adjusted Personalized Therapy Comparing Trastuzumab-deruxtecan Versus Pacli-/Docetaxel+Carboplatin+Trastuzumab+Pertuzumab in HER2+ Early Breast Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: HER2-positive Early Breast Cancer
Keywords: HER2+
T-DXd
Trastuzumab-deruxtecan
pCR
intermediate risk
high risk
low risk
recurrence
neoadjuvant
Lead sponsor: West German Study Group
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2023-01-30
Enrollment: 402
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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

Brief 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.

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.

Primary outcomes:
measure: 1. pCR rate after neoadjuvant treatment
timeFrame: after 12 weeks of neoadjuvant treatment
measure: 1. pCR rate after neoadjuvant treatment
timeFrame: after 18 weeks of neoadjuvant treatment
measure: 2. distant disease-free survival (dDFS, according to STEEP 2.0 criteria)
timeFrame: after 3 years
Secondary outcomes:
measure: clinical response
timeFrame: after 6 weeks of treatment
measure: clinical response
timeFrame: after 12 weeks of treatment
measure: clinical response
timeFrame: after 18 (cohort 2) weeks of treatment
measure: dDFS in patients with pCR
timeFrame: after 3 years
measure: pCR rates after different treatment durations
timeFrame: 12 versus 18 weeks
measure: pCR rates in T-DXd 12 weeks versus PAC+T+P
timeFrame: after 12 weeks
measure: pCR rates in T-DXd 18 weeks versus PAC/DOC+Carbo+T+P
timeFrame: after 18 weeks
measure: iDFS
timeFrame: at end of study
measure: OS
timeFrame: at end of study
measure: LRFS
timeFrame: at end of study
measure: BCFS
timeFrame: at end of study
measure: DRFI
timeFrame: at end of study
measure: QOL
timeFrame: after 1 year
Other outcomes:
Locations:
city: Baden-Baden
country: Germany
facility: Klinikum Mittelbaden, Brustzentrum
state: Baden-Württemberg
city: Freiburg
country: Germany
facility: Praxis für Interdisziplinäre Onkologie und Hämatologie (PIO)
state: Baden-Württemberg
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
state: Baden-Württemberg
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
state: Baden-Württemberg
city: Munich
country: Germany
facility: Breast Center of the University of Munich (LMU) Universitätsfrauenklinik
state: Bavaria
city: Augsburg
country: Germany
facility: Hämotologisch onkologische Praxis Heinrich Bangerter Augsburg GbR
state: Bayern
city: Augsburg
country: Germany
facility: Universitätsklinikum Augsburg / Klinik für Frauenheilkunde und Geburtshilfe
state: Bayern
city: Muenchen
country: Germany
facility: Rotkreuz Klinikum München
state: Bayern
city: Bremerhaven
country: Germany
facility: Klinikum Bremerhaven Reinkenheide
state: Bremen
city: Rostock
country: Germany
facility: Universittsklinikum am Klinikum Südstadt
state: ecklenburg-Vorpommerns
city: Frankfurt am Main
country: Germany
facility: AGAPLESION Markus Krankenhaus Gynäkologie
state: Hessen
city: Frankfurt am Main
country: Germany
facility: Klinikum Frankfurt Höchst GmbH
state: Hessen
city: Kassel
country: Germany
facility: Klinikum Kassel
state: Hessen
city: Braunschweig
country: Germany
facility: Studien GbR Braunschweig
state: Niedersachsen
city: Georgsmarienhütte
country: Germany
facility: Niels-Stensen-Kliniken Franziskus-Hospital
state: Niedersachsen
city: Hildesheim
country: Germany
facility: Ärztehaus am Bahnhofsplatz
state: Niedersachsen
city: Stade
country: Germany
facility: MVZ Klinik Dr. Hancken GmbH
state: Niedersachsen
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen
state: NRW
city: Bielefeld
country: Germany
facility: Onkologische Schwerpunktpraxis Bielefeld
state: NRW
city: Düsseldorf
country: Germany
facility: Kliniken für Frauenheilkunde / Universitätsklinikum Düsseldorf
state: NRW
city: Düsseldorf
country: Germany
facility: Luisenkrankenhaus GmbH
state: NRW
city: Eschweiler
country: Germany
facility: Sankt-Antonius-Hospital
state: NRW
city: Essen
country: Germany
facility: Kliniken Essen-Mitte, Klinik für Senologie/Interdisziplinäres Brustzentrum
state: NRW
city: Essen
country: Germany
facility: Universitätsklinikum Essen, Brustzentrum
state: NRW
city: Gütersloh
country: Germany
facility: Onkodok Gütersloh
state: NRW
city: Hamm
country: Germany
facility: St. Barbara Klinik
state: NRW
city: Köln
country: Germany
facility: St. Elisabeth Krankenhaus GmbH
state: NRW
city: Köln
country: Germany
facility: Kliniken der Stadt Köln GmbH / Brustzentrum Holweide
state: NRW
city: Moenchengladbach
country: Germany
facility: Brustzentrum Niederrhein, Johanniter Bethesda Krankenhaus
state: NRW
city: Münster
country: Germany
facility: MVZ Media Vita am St. Franziskus Hospital
state: NRW
city: Paderborn
country: Germany
facility: Frauenklinik St. Louise-St. Vincenz-KH GmbH
state: NRW
city: Schwerte
country: Germany
facility: MKS St. Paulus GmbH
state: NRW
city: Troisdorf
country: Germany
facility: Praxisnetzwerk Hämatologie und intern. Onkologie
state: NRW
city: Wuppertal
country: Germany
facility: Helios-Klinik Wuppertal
state: NRW
city: Trier
country: Germany
facility: Klinikum Mutterhaus
state: Rheinland-Pfalz
city: Saarbrücken
country: Germany
facility: CaritasKlinikum Saarbrücken St. Theresia
state: Saarland
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
state: Sachsen
city: Rodewisch
country: Germany
facility: Frauenklinik / Brustzentrum am Klinikum Obergölzsch Rodewisch
state: Sachsen
city: Lübeck
country: Germany
facility: UK Schleswig Holstein
state: Schleswig-Holsteins
city: Berlin
country: Germany
facility: Charite Campus Mitte
city: Berlin
country: Germany
facility: Ev. Waldkrankenhaus Spandau
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf / Klinik und Poliklinik für Gynäkologie
city: Hamburg
country: Germany
facility: Brustzentrum am Krankenhaus Jerusalem
Study officials:
affiliation: Breast Centre, Dept. Obstetrics & Gynaecology and CCC Munich LMU University Hospital
name: Nadia Harbeck, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Breast Centre, Kliniken Essen Mitte Essen
name: Sherko Kuemmel, PRof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Breast Centre, Evang. Bethesda-Hospital Moenchengladbach
name: Oleg Gluz, PD Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Breast Centre Rotkreuzklinikum Munich
name: Michael Braun, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Breast Centre, Evang. Bethesda-Hospital Moenchengladbach
name: Monika Graeser, PD Dr.
role: PRINCIPAL_INVESTIGATOR
References: