De-escalation Adjuvant Chemo in HER2+/ER-/node-neg Early BC Patients Who Achieved PCR After Neoadjuvant Chemo & Dual HER2 Blockade
NCT ID: NCT04675827
Last Updated: 2024-12-04
Study Results
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Basic Information
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TERMINATED
PHASE2
139 participants
INTERVENTIONAL
2022-01-17
2024-11-26
Brief Summary
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Surgery will be performed according to local guidelines in all subjects after neoadjuvant treatment.
After surgery, subjects who achieve a pCR (defined as pT0/Tis pN0) will receive adjuvant pertuzumab and trastuzumab FDC SC for additional 14 cycles. Subjects with residual invasive disease will receive salvage adjuvant trastuzumab emtansine (T-DM1, 3.6 mg/kg, IV every 3 weeks) for 14 cycles. In subjects whose residual invasive disease is classified per RCB score as ≥2, 3 to 4 cycles of anthracycline-based chemotherapy may be administered, at the investigator's discretion, before the 14 cycles of T-DM1.
If histopathological analysis finds that the surgical specimen from a subject with residual disease is ER-positive and/or PR-positive, adjuvant endocrine therapy may be administered concomitantly with study treatment, at the investigator's discretion and according to local guidelines.
Adjuvant radiotherapy will be mandatory after breast-conserving surgery, whereas it will be performed according to local guidelines after mastectomy, and it will be administered concomitantly with pertuzumab and trastuzumab FDC SC in subjects who achieve a pCR, and concomitantly with T-DM1 in subjects with residual invasive disease (after anthracycline-based chemotherapy in subjects assigned to receive this treatment).
Detailed Description
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Surgery will be performed according to local guidelines in all subjects after neoadjuvant treatment.
After surgery, subjects who achieve a pathologic complete response (pCR, defined as pT0/Tis pN0) will receive adjuvant pertuzumab and trastuzumab FDC SC for additional 14 cycles. Subjects with residual invasive disease will receive salvage adjuvant trastuzumab emtansine (T-DM1, 3.6 mg/kg, IV every 3 weeks) for 14 cycles. In subjects whose residual invasive disease is classified per Residual Cancer Burden (RCB) score as ≥2, 3 to 4 cycles of anthracycline-based chemotherapy may be administered, at the investigator's discretion, before the 14 cycles of T-DM1.
If histopathological analysis finds that the surgical specimen from a subject with residual disease is ER-positive and/or PR-positive, adjuvant endocrine therapy may be administered concomitantly with study treatment, at the investigator's discretion and according to local guidelines.
Adjuvant radiotherapy will be mandatory after breast-conserving surgery, whereas it will be performed according to local guidelines after mastectomy, and it will be administered concomitantly with pertuzumab and trastuzumab FDC SC in subjects who achieve a pCR, and concomitantly with T-DM1 in subjects with residual invasive disease (after anthracycline-based chemotherapy in subjects assigned to receive this treatment).
Patients' tumour intrinsic subtype will be determined based on analysis of the PAM50 gene signature. The PAM50 gene signature, which measures the expression of 50 genes to classify tumours into 1 of 4 intrinsic subtypes (luminal A, luminal B, HER2-enriched, and basal-like), will be assessed in formalin-fixed paraffin embedded (FFPE) samples obtained at baseline. While a tumour biopsy sample must be available prior to enrolment, the PAM50 results will be generated centrally post enrolment and subsequently used to assess the primary endpoint of the study, which is the 3-year recurrence-free survival (RFS) rate in the subpopulation of subjects with HER2-enriched tumours who achieve a pCR after the neoadjuvant phase of the study.
Sub-study:
The flexible care sub-study is an open-label, randomised phase II study to be conducted in selected sites from some of the countries that participate in DECRESCENDO. After completion of neoadjuvant treatment and surgery in the main study, 121 of the subjects who achieved a pCR and thus are assigned to continue treatment with pertuzumab and trastuzumab FDC SC will be randomised at a 1:1 ratio to receive 3 cycles of pertuzumab and trastuzumab FDC SC every 3 weeks in the hospital, followed by 3 cycles in another setting outside the hospital, or to the same treatment starting with 3 cycles outside the hospital followed by 3 cycles in the hospital (treatment cross-over period). After the first 6 cycles of adjuvant treatment, subjects will be asked to choose between continuing treatment (for the remaining 8 cycles, for a total of 14 cycles) within or outside the hospital, according to their preference (treatment continuation period). Subjects can request to change from outside the hospital to in the hospital administration (and vice-versa) at any moment during the treatment continuation period, but not in the treatment cross-over period.
Conditions
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Study Design
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NON_RANDOMIZED
SEQUENTIAL
TREATMENT
NONE
Study Groups
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RCB = 0
Treatment administration: adjuvant pertuzumab + trastuzumab (P+T) fixed dose combination (FDC) SC for 14 cycles.
Sub-study: 121 of the subjects who achieved a pCR (thus assigned to continue treatment with P+T FDC SC) will be randomised at a 1:1 ratio to receive 3 cycles of P+T FDC SC in the hospital, followed by 3 cycles in another setting outside the hospital, or to the same treatment starting with 3 cycles outside the hospital followed by 3 cycles in the hospital (treatment cross-over period). After the first 6 cycles of adjuvant treatment, subjects will be asked to choose between continuing treatment (for the remaining 8 cycles, for a total of 14 cycles) within or outside the hospital, according to their preference (treatment continuation period). Subjects can request to change from outside the hospital to in the hospital administration (and vice-versa) at any moment during the treatment continuation period, but not in the treatment cross-over period.
Pertuzumab and tratuzumab fixed dose combination
Treatment administration: adjuvant pertuzumab and trastuzumab fixed dose combination SC for 14 cycles
RCB > 0
Treatment administration:adjuvant T-DM1 for 14 cycles. In subjects whose residual invasive disease is classified per Residual Cancer Burden (RCB) score as ≥2, 3 to 4 cycles of anthracycline-based chemotherapy may be administered, at the investigator's discretion, before the 14 cycles of T-DM1.
Trastuzumab emtansine
Treatment administration: adjuvant T-DM1 for 14 cycles.
Interventions
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Pertuzumab and tratuzumab fixed dose combination
Treatment administration: adjuvant pertuzumab and trastuzumab fixed dose combination SC for 14 cycles
Trastuzumab emtansine
Treatment administration: adjuvant T-DM1 for 14 cycles.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Age ≥18 years old.
3. Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
4. Subjects whose tumour measures ≥15 mm and ≤50 mm, according to clinical staging performed with imaging exams (either mammography, ultrasound or breast magnetic resonance imaging \[MRI\]).
5. Must have histologically confirmed diagnosis of HER2-positive and ER-negative/PR-negative breast cancer (analysis performed by the local laboratory).
1. HER2-positive defined as a score of 3+ in IHC or a positive ISH (ratio of HER2 copy number/chromosome 17 ≥2 or average HER2 copy number ≥6 signals per cell).
2. ER-negative/PR-negative defined as estrogen receptor and progesterone receptor nuclear staining \<1% by IHC.
Note: patients with micro-invasive carcinoma or ductal carcinoma in situ (DCIS) without invasive disease are not eligible.
6. Subjects with multifocal or multicentric invasive disease are eligible as long as all the biopsiable lesions can be characterised and are confirmed to be HER2-positive and ER and PR negative.
Note: In the case of multifocal or multicentric disease, only the biopsy from the largest lesion should be provided.
7. Node-negative disease (N0): no axillary lymph nodes identifiable at ultrasound, or in case of suspect axillary lymph nodes are identified, fine-needle aspiration or core biopsy must be carried out to confirm that axillary status is negative. Axillary micrometastases (i.e., if the greatest diameter of the nodal metastasis in a sentinel node is 0.2 mm or less) are not allowed.
8. Serum pregnancy test (for women of childbearing potential) negative within 7 days prior to treatment start.
9. Women of childbearing potential must agree to use 1 highly effective non-hormonal contraceptive method with a failure rate of less than 1% per year from the signing of the ICF until at least 7 months after last dose of study drugs; or they must totally abstain from any form of sexual intercourse. Men with a partner of childbearing potential must agree to use condom in combination with a spermicidal foam, gel, film, cream, or suppository, and agreement to refrain from donating sperm, during the course of this study and for at least 7 months after the last administration of study treatment.
10. Adequate bone marrow and coagulation functions as defined below:
* Absolute neutrophil count ≥1500 /µL or 1.5x109/L
* Haemoglobin ≥9 g/dL (blood transfusions to reach these levels of haemoglobin are allowed)
* Platelets ≥100,000/µL or 100x109/L
* International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 ×ULN
11. Adequate liver function as defined below:
* Serum total bilirubin ≤1.5 x ULN. In case of known Gilbert's syndrome ≤3xUNL is allowed
* AST (SGOT) and ALT (SGPT) ≤2.5 x ULN
* Alkaline phosphatase ≤2.5 x ULN
12. Adequate renal function as defined below:
• Creatinine ≤1.5 x UNL or creatinine clearance \>60 mL/min/1.73 m2
13. Completion of all necessary screening procedures within 28 days prior to enrolment.
14. Adequate cardiac function, defined as a left ventricular ejection fraction ≥55% estimated by echocardiogram (ECHO) or multiple-gated acquisition scintigraphy (MUGA).
15. Availability of a pre-treatment tumour biopsy sample as specified below:
* At least one FFPE tumour block must be available for central evaluation. Whenever possible, two FFPE tumour blocks should be available (preferred).
* If a block cannot be provided, 25 unstained FFPE slides of 4 µm thickness from the pre-treatment tumour biopsy must be provided as an alternative. These slides must be freshly cut prior the shipment to the sponsor.
* In either case, the local pathologist must evaluate an H\&E stained slide to ensure that the tumour surface is at least 4 mm² and that tumour cellularity is ≥10%.
Note 1: Tumour biopsy must be sent to the central research laboratory as soon as the patient is confirmed by the local investigator to be eligible for the study.
Note 2: the inclusion of the subject is only based on local assessments. A central review of HER2, ER, and PR status will be performed at posteriori for quality control purposes.
16. Signed Informed Consent form (ICF) obtained prior to any study related procedure.
17. Subject is willing and able to comply with the protocol for the duration of the study including treatment and scheduled visits and examinations.
Inclusion criterion applicable to FRANCE only:
18. Affiliated to the French Social Security System.
Exclusion Criteria
2. Bilateral invasive breast cancer.
3. Evidence of metastatic breast cancer: all subjects must have had a CT/MRI scan of the thorax/abdomen/pelvis to rule out metastatic breast cancer prior to enrolment. FDG/PET-CT can be used as an alternative to replace all the exams above. A screening bone scan must have been done if ALP and/or corrected calcium levels were above the institutional upper limits at screening (if PET/CT was used as an alternative imaging exam, a bone scan and/or CT/MRI is not required).
4. Subject with a significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the investigator's opinion, may interfere with completion of the study.
5. Previous exposure to any anti-HER2 treatment.
6. Concomitant exposure to any investigational products as part of a clinical trial within 30 days prior to enrolment.
7. Subject with second primary malignancies diagnosed ≤ 5 years before enrolment in the study. Exceptions are: adequately treated non-melanoma skin cancer, in situ cancer of the cervix, ductal carcinoma in situ of the breast, and any other solid or haematological tumour diagnosed \> 5 years before enrolment and for which no chemotherapy and no systemic treatment were necessary, with no evidence of disease recurrence.
8. Resting electrocardiogram (ECG) with QTc \>470 msec detected on at 2 or more time points within a 24-hour period, or family history of long QT syndrome.
9. Serious cardiac illness or medical conditions including, but not confined to, the following:
* History of NCI CTCAE (v4) Grade ≥ 3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) Class ≥ II
* High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate = or \> 100/min at rest, significant ventricular arrhythmia \[ventricular tachycardia\], or higher-grade atrioventricular \[AV\]-block, such as second degree AV-block Type 2 \[Mobitz 2\] or third-degree AV-block) - Serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality
* Angina pectoris requiring anti-anginal medication
* Clinically significant valvular heart disease
* Evidence of transmural infarction on ECG
* Evidence of myocardial infarction within 12 months prior to randomization
* Poorly controlled hypertension (i.e., systolic \> 180 mm Hg or diastolic \> 100 mmHg)
10. History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease (e.g., severe LVSD, left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome.
11. Peripheral neuropathy (CTCAE version 5) grade ≥2.
12. Major surgery within 14 days prior to enrolment.
13. Subject with HIV, Hepatitis B or Hepatitis C infection documented by serology, except for those subjects with a previous exposure to Hepatitis B who developed an effective immune response (HBSAg-negative and anti-HBS-positive).
14. Previous allogeneic bone marrow transplant.
15. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (CTCAE grade ≥3).
16. Subjects who received live attenuated vaccines within 14 days before enrolment.
Exclusion criterion applicable to FRANCE only:
17. Vulnerable persons according to the article L.1121-6 of the CSP, adults who are the subject of a measure of legal protection or unable to express their consent according to article L.1121-8 of the CSP.
18 Years
ALL
No
Sponsors
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Breast International Group
OTHER
Hoffmann-La Roche
INDUSTRY
International Drug Development Institute
OTHER
Institut Curie
OTHER
Jules Bordet Institute
OTHER
Responsible Party
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Principal Investigators
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Martine Piccart, PD, PhD
Role: STUDY_CHAIR
Jules Bordet Institute
Locations
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Icon Cancer Centre Wesley
Auchenflower, , Australia
Ballarat Health Services
Ballarat, , Australia
Bendigo Hospital
Bendigo, , Australia
Sunshine Coast University Hospital
Birtinya, , Australia
Box Hill Hospital
Box Hill, , Australia
Chris O'Brien Lifehouse
Camperdown, , Australia
Monash Medical Centre (Clayton)
Clayton, , Australia
Coffs Harbour Health Campus
Coffs Harbour, , Australia
Concord Repatriation General Hospital
Concord, , Australia
Townsville University Hospital
Douglas, , Australia
Lake Macquarie Private Hospital
Gateshead, , Australia
Gosford Hospital
Gosford, , Australia
Royal Brisbane and Women's Hospital
Herston, , Australia
Icon Cancer Centre Hobart
Hobart, , Australia
Liverpool Hospital
Liverpool, , Australia
Peter MacCallum Cancer Centre
Melbourne, , Australia
Sir Charles Gairdner Hospital
Nedlands, , Australia
Macquarie University
North Ryde, , Australia
Mater Hospital
North Sydney, , Australia
Sunshine Hospital
Saint Albans, , Australia
Calvary Mater Newcastle
Waratah, , Australia
Westmead Hospital
Westmead, , Australia
Princess Alexandra Hospital
Woolloongabba, , Australia
GZA Ziekenhuisen Campus Sint-Augustinus - Iridium Kankernetwerk
Antwerp, Wilrijk, Belgium
OLV ziekenhuis
Aalst, , Belgium
Cliniques Universtaires Saint-Luc
Brussels, , Belgium
Institut Jules Bordet
Brussels, , Belgium
Grand Hôpital de Charleroi
Charleroi, , Belgium
Heilig Hartziekenhuis
Lier, , Belgium
Centre Hospitalier Chretien MontLegia
Liège, , Belgium
CHU UCL Namur Sainte-Elisabeth
Namur, , Belgium
Institut de Cancérologie de l'Ouest - Angers
Angers, , France
Institut Sainte Catherine
Avignon, , France
Centre Hospitalier de la Côte Basque
Bayonne, , France
CHRU Jean Minjoz
Besançon, , France
Institut Bergonié
Bordeaux, , France
Polyclinique Bordeaux Nord Aquitaine
Bordeaux, , France
CHU Morvan
Brest, , France
Centre François Baclesse
Caen, , France
Centre Jean Perrin
Clermont-Ferrand, , France
Centre Georges François Leclerc
Dijon, , France
Hopital Michallon
Grenoble, , France
Centre Oscar Lambret
Lille, , France
CHU de Limoges
Limoges, , France
GHBS Lorient
Lorient, , France
Centre Léon Bérard
Lyon, , France
Institut Paoli Calmettes
Marseille, , France
CH Annecy Genevois
Metz-Tessy, , France
Centre de Cancerologie du Grand Montpellier
Montpellier, , France
Hopital privé du Confluent
Nantes, , France
Groupe Hospitalier Diaconesses Croix Saint-Simon
Paris, , France
Hopital Tenon
Paris, , France
Institut Curie - Paris
Paris, , France
CH Perpignan
Perpignan, , France
Hopital Lyon Sud
Pierre-Bénite, , France
CHU Poitiers
Poitiers, , France
Institut Godinot
Reims, , France
Centre Henri Becquerel
Rouen, , France
Institut Curie - Saint-Cloud
Saint-Cloud, , France
Clinique Saint Anne
Strasbourg, , France
Institut Claudius Regaud
Toulouse, , France
Institut Gustave Roussy
Villejuif, , France
Sheba Medical Center
Ramat Gan, , Israel
Soon Chun Hyang University Cheonan Hospital
Cheonan, , South Korea
Keimyung University Dongsan Hospital
Daegu, , South Korea
National Cancer Center
Goyang-si, , South Korea
Gachon University Gil Medical Center
Incheon, , South Korea
Inha University Hospital
Incheon, , South Korea
Seoul National University Bundang Hospital
Seongnam, , South Korea
CHA bundang Medical Center
Seongnam-si, , South Korea
Asan Medical Center
Seoul, , South Korea
Ewha Womans University Mokdong Hospital
Seoul, , South Korea
Korea university anam hospital
Seoul, , South Korea
Samsung Medical Center
Seoul, , South Korea
Seoul National University Hospital
Seoul, , South Korea
Seoul ST. Mary's Hospital
Seoul, , South Korea
Severance Hospital
Seoul, , South Korea
Ajou University Hospital
Suwon, , South Korea
Ulsan University Hospital
Ulsan, , South Korea
Hirslanden Klinik - Tumor Zentrum
Aarau, , Switzerland
Kantonsspital Baden
Baden, , Switzerland
Universitatsspital Basel
Basel, , Switzerland
Kantonsspital Frauenfeld/Frauenklinik
Frauenfeld, , Switzerland
Hopital Daler - Centre du Sein
Fribourg, , Switzerland
Kantonsspital Winterthur
Winterthur, , Switzerland
Countries
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Other Identifiers
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IJB-EBC-Decrescendo-2020
Identifier Type: -
Identifier Source: org_study_id