Adj. Marker-adjusted Personalized Therapy Comparing ET+Ribociclib vs Chemotherapy in Intermediate Risk, HR+/HER2- EBC
- Conditions
- Breast Cancer Female
- Interventions
- Registration Number
- NCT04055493
- Lead Sponsor
- West German Study Group
- Brief Summary
The study investigates, whether the patient group with intermediate-risk early breast cancer benefits from treatment with ribociclib in combination with endocrine therapy compared to standard-of-care chemotherapy (followed by adjuvant endocrine therapy).
- Detailed Description
The WSG ADAPT trial program is one of the first new generation trials addressing the issue of individualization of (neo)-adjuvant decision-making in early breast cancer (EBC) in a subtype-specific manner. The first WSG ADAPT umbrella trial (NCT01779206) aimed to establish early predictive molecular surrogate markers for response after a short 3-week induction treatment.
The goals of the WSG ADAPT trial program - early response assessment and subtype-specific therapy tailoring to those patients who are most likely to benefit - have contributed to the very positive national and international feedback to the ADAPT concept as a whole.
The aim of this ADAPTcycle phase-III-trial is to investigate whether the intermediate-risk patient group identified during the screening phase derives additional benefit from treatment with ribociclib in combination with ET compared to chemotherapy (followed by adjuvant ET).
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Female
- Target Recruitment
- 1684
Patients eligible for inclusion in this study have to meet all of the following criteria:
A. Prior to REGISTRATION in the study:
- Written informed consent prior to any screening procedures. 2. Female. 3. ≥ 18 years of age. 4a. EITHER: (Post)menopausal status at the time of initiation of (neo)adjuvant study medication
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patient underwent bilateral oophorectomy, or
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age ≥ 60, or
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age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and/or FSH and estradiol in the postmenopausal range per local normal range.
4b. OR: Pre-menopausal patients:
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confirmed negative serum pregnancy test (β-hCG) before starting study treatment, or
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patient has had a hysterectomy. 5. Histologically confirmed diagnosis of primary estrogen-receptor positive and/or progesterone-receptor positive (> 1%) early breast cancer by local laboratory.
- Patient has HER2-negative breast cancer defined as
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a negative in-situ hybridization test or an IHC status of 0, 1+, or 2+,
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if IHC is 2+, a negative in-situ hybridization (FISH, CISH, or SISH) test is required (based on the most recently analyzed tissue sample and all tested by a local laboratory).
- Local therapy of breast cancer (if adjuvant treatment or planned if neoadjuvant treatment) according to current guidelines.
Note: This may include radiotherapy of breast cancer.
B. Prior to RANDOMIZATION in the study 8. No evidence of distant metastasis (confirmed prior to randomization by, preferentially, CT thorax / abdomen, X-ray chest, ultrasound liver, bone scan, or PET-CT).
- Patient has available tumor tissue from diagnostic biopsy. 10. Patient is classified as intermediate risk according to the ADAPT intermediate-risk definition (i) (as follows), or (only in case of missing Oncotype DX or Ki-67 response data), according to the clinical intermediate-risk definition (ii) (as follows).
(i). ADAPT intermediate-risk definition: Patient meets one of the following criteria:
- c/pN0, RS ≤ 25 with luminal-B-like (Ki-67 ≥20% or G3) or c/pT2-4 without endocrine response (post-endocrine Ki-67 > 10 %)
- c/pN1, RS ≤ 25 without endocrine response (post-endocrine Ki-67 > 10 %)
- c/pN0, RS > 25 with luminal-B-like (Ki-67 ≥20% or G3) or c/pT2-4 with endocrine response (Ki-67 ≤ 10 %)
- c/pN1, RS > 25 with endocrine response (Ki-67 ≤ 10 %)
- c/pN2-3, RS ≤ 25 with endocrine response (Ki-67 ≤ 10 %). Note: Postmenopausal patients with pT1-2/pN0 disease and RS < 25, as well as premenopausal patients with pT1-2/pN0 disease and RS<16, are recommended to be treated by endocrine therapy alone and not to be randomized (at investigator´s discretion).
(ii). Clinical intermediate-risk definition (ascertained by investigator): Clinical intermediate risk may be ascertained by the investigator prior to randomization if at maximum two of the following three risk factors are present (according to primary diagnosis / 1st sample):
-
cT2-4
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c/pN positive
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G3 and / or Ki-67 ≥ 20% Note: Inclusion of a patient according to "clinical intermediate risk" is permitted only in case of missing baseline Oncotype DX® or Ki-67 decrease. In this case, investigators will follow a risk-based, step-wise assessment process.
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No contraindication for (neo)-adjuvant ET. 12. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 13. Patient has adequate bone marrow and organ function as defined by the following laboratory values:
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absolute neutrophil count ≥ 1.5 × 109/L,
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platelets ≥ 100 × 109/L,
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hemoglobin ≥ 9.0 g/dL,
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estimated glomerular filtration rate (eGFR) ≥ 30 mL/min by a Cockcroft-Gault formula,
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INR ≤ 1.5,
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serum creatinine < 1.5 mg/dL,
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total bilirubin < ULN, except for patients with Gilbert's Syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN,
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aspartate transaminase (AST) < 2.5 × ULN,
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alanine transaminase (ALT) < 2.5 × ULN. 14. 2-lead-ECG (CANKADO) with:
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QTcF interval at screening < 450 msec (using Fridericia's correction),
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mean resting heart rate 50-90 bpm (determined from the ECG). 15. Ability to swallow ribociclib tablets or to administer other study medication, respectively.
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Ability to communicate with the investigator and comply with study procedures.
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Willing to remain during therapy at the clinical site, as required by the protocol.
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Patients eligible for inclusion in this study must not meet any of the following criteria:
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Patient with distant metastases of breast cancer beyond regional lymph nodes.
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Patient has received prior (neo)-adjuvant treatment with chemotherapy, ET, or any CDK4/6 inhibitor for breast cancer.
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Patient has received tamoxifen, raloxifene, or aromatase inhibitors (AIs) for reduction in risk ("chemoprevention") of breast cancer and/or treatment for osteoporosis within last 2 years prior to screening.
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Patient has received prior neoadjuvant/adjuvant treatment with anthracyclines at cumulative doses of 450 mg/m² or more for doxorubicin or 900 mg/m² or more for epirubicin.
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Patient with a known hypersensitivity to any of the excipients of ribociclib, ET, or standard-of-care chemotherapy.
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Patient with inflammatory breast cancer at screening.
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Patient is concurrently using other anti-cancer therapy.
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Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.
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Patient is currently receiving warfarin or other coumarin-derived anti-coagulant for treatment, prophylaxis, or otherwise.
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Patient has not recovered from clinical and laboratory acute toxicities related to prior anticancer therapies to NCI CTCAE version 5.0 Grade ≤ 1.
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Patient has a concurrent malignancy, or malignancy within 5 years of randomization, or known history of invasive breast cancer.
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Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small-bowel resection).
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Patient has a known history of HIV infection.
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Patient has known active hepatitis-B-virus (HBV) or hepatitis-C-virus (HCV) infection.
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Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator´s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study, or compromise compliance with the protocol (e.g., chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial, or viral infections, etc.).
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Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:
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history of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry,
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documented cardiomyopathy,
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left ventricular ejection fraction (LVEF) < 50 % as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO),
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long QT syndrome, family history of idiopathic sudden death, congenital long QT syndrome, or any of the following:
- risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/ symptomatic bradycardia,
- concomitant medications with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication (e.g., within 5 half-lives or 7 days prior to starting study drug),
- inability to determine the QTcF interval,
- clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left-bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II, and 3rd-degree AV block),
- systolic blood pressure (SBP) > 160 or < 90 mmHg.
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Patient is currently receiving any of the following substances, which cannot be discontinued 7 days prior to Cycle 1 Day 1:
- concomitant medications, herbal supplements, fruits (e.g. grapefruit, pomegranates, pomelos, star fruit, Seville oranges) and their juices that are strong inducers or inhibitors of CYP3A4/5,
- medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
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Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment.
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Participation in a prior investigational study within 30 days prior to enrollment or within five half-lives of the investigational product, whichever is longer.
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Not able to understand and to comply with study instructions and requirements.
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Pregnant or nursing (lactating) woman.
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Woman of child-bearing potential defined as woman physiologically capable of becoming pregnant, unless she is using highly effective methods of contraception during the study treatment and for 21 days after stopping the treatment:
- total abstinence (when this is in line with the preferred and usual lifestyle of the patient).
- female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment.
- male partner sterilization (at least 6 months prior to study screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient.
- placement of an intrauterine device (IUD).
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Use of oral (estrogen and progesterone), transdermal, injected, or implanted hormonal methods of contraception as well as hormonal replacement therapy.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Ribociclib plus ET Ribociclib 200Mg Oral Tablet Ribociclib 600mg / day over 26 cycles + endocrine treatment of physician´s choice
- Primary Outcome Measures
Name Time Method invasive disease-free survival (iDFS) at end of study, on average 5 years after start of treatment superiority in invasive disease-free survival (iDFS) of ribociclib + ET vs. standard-of-care chemotherapy
distant disease-free survival (dDFS) at end of study, on average 5 years after start of treatment distant disease-free survival (dDFS) in the ribociclib + ET-group to demonstrate survival rate \>92%
- Secondary Outcome Measures
Name Time Method overall survival (OS) 95 % CI at end of study, on average 5 years after start of treatment 95 %-confidence interval (CI) for OS in both arms
distant disease-free survival (dDFS) 95 % CI at end of study, on average 5 years after start of treatment 95 %-confidence interval (CI) for dDFS in both arms
QoL at end of study, on average 5 years after start of treatment quality of life (QoL) and correlation to treatment-related symptoms measured by EQ-VAS and triggered symptom questionnaire,
treatment adherence at end of study, on average 5 years after start of treatment treatment adherence measured by drug intake compared between treatment arms
pathological complete response (pCR) at end of study, on average 5 years after start of treatment Pathological response rate (defined as ypT0/is/ypN0), as well as further definitions (ypT0/ypN0; ypT0/is/any ypN, near pCR (ypT1a/any ypN)), in neoadjuvant treated patients
clinical response rate at end of study, on average 5 years after start of treatment clinical response rate (by palpation, ultrasound, and further methods) compared between treatment arms
rate of breast-conservation therapy at end of study, on average 5 years after start of treatment prevalence of breast conservation therapy vs. mastectomy compared between treatment arms
Trial Locations
- Locations (86)
Ost-Alb Klinikum Brustzentrum
🇩🇪Aalen, Baden-Württemberg, Germany
Stadtklinik Baden-Baden Brustzentrum
🇩🇪Baden-Baden, Baden-Württemberg, Germany
Kreiskliniken Böblingen Klinikum Böblingen Frauenklinik
🇩🇪Böblingen, Baden-Württemberg, Germany
Uniklinikum Freiburg Frauenklinik
🇩🇪Freiburg, Baden-Württemberg, Germany
Praxis für interdisziplinäre Onkologie & Hämatologie GbR Praxis am Diakonieklinikum
🇩🇪Freiburg, Baden-Württemberg, Germany
SLK-Kliniken-Heilbronn Frauenklinik
🇩🇪Heilbronn, Baden-Württemberg, Germany
Klinikum Ludwigsburg Klinik für Frauenheilkunde u. Geburtshilfe
🇩🇪Ludwigsburg, Baden-Württemberg, Germany
Universitätsklinikum Tübingen Universitäts-Frauenklinik
🇩🇪Tübingen, Baden-Württemberg, Germany
Universitätsfrauenklinik Ulm Frauenheilkunde und Geburtshilfe
🇩🇪Ulm, Baden-Württemberg, Germany
GRN Klinik Weinheim Gynäkologie
🇩🇪Weinheim, Baden-Württemberg, Germany
Klinikum der Universität München Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Brustzentrum
🇩🇪Munich, Bavaria, Germany
Rotkreuzkliniken München Frauenklinik - Gynäkologie
🇩🇪München, Bavaria, Germany
Frauenklinik und Poliklinik / Studienzentrale Josef-Schneider-Straße 4
🇩🇪Würzburg, Bavaria, Germany
Carl-Thiem-Klinikum / Brustzentrum Senologie der Frauenklinik
🇩🇪Cottbus, Brandenburg, Germany
Schwerpunktpraxis Gynäkologische Onkologie Praxis Dr. Heinrich
🇩🇪Fürstenwalde, Brandenburg, Germany
Klinikum Ernst von Bergmann Klinik für Gynäkologie und Geburtshilfe
🇩🇪Potsdam, Brandenburg, Germany
Klinikum Bremerhaven Reinkenheide Frauenklinik
🇩🇪Bremerhaven, Bremen, Germany
Klinikum Frankfurt Höchst Klinik für Gynäkologie und Geburtshilfe
🇩🇪Frankfurt am Main, Hesse, Germany
AGAPLESION Markus Krankenhaus / Brustzentrum Gynäkologie und Geburtshilfe
🇩🇪Frankfurt, Hesse, Germany
Klinikum Kassel Frauenklinik
🇩🇪Kassel, Hesse, Germany
Sana Klinikum Klinik für Gynäkologie und Geburtshilfe, Studienambulanz AOZ
🇩🇪Offenbach, Hesse, Germany
St. Josefs-Hospital Wiesbaden Frauenklinik - Gynäkologie
🇩🇪Wiesbaden, Hesse, Germany
Frauenärzte Casparistraße Studien GbR BS
🇩🇪Braunschweig, Lower Saxony, Germany
MVZ II der Niels Stensen Kliniken Onkologie u. Hämatologie, Brustzenzrum
🇩🇪Georgsmarienhütte, Lower Saxony, Germany
Medizinische Hochschulle Hannover Klinik für Frauenheilkunde und Geburtshilfe
🇩🇪Hannover, Lower Saxony, Germany
DIAKOVERE Henriettenstift Frauenklinik
🇩🇪Hannover, Lower Saxony, Germany
Gynäkologische Gemeinschaftspraxis-Ärztehaus am Bahnhofsplatz Klinische Studien
🇩🇪Hildesheim, Lower Saxony, Germany
Städtisches Klinikum Lüneburg Frauenklinik
🇩🇪Lüneburg, Lower Saxony, Germany
MVZ Klinik Dr. Hancken Haematologie/Onkologie
🇩🇪Stade, Lower Saxony, Germany
UFK Klinikum Südstadt Frauenklinik
🇩🇪Rostock, Mecklenburg-Vorpommern, Germany
Marienhospital Studienzentrale BrustCentrum Aachen-Kreis Heinsberg
🇩🇪Aachen, NRW, Germany
Universitätsklinikum Aachen, Frauenklinik - Senologie
🇩🇪Aachen, NRW, Germany
EVK Bergisch Gladbach Brustzentrum
🇩🇪Bergisch-Gladbach, NRW, Germany
Onkologische Schwerpunktpraxis Bielefeld Praxis Dr. Just
🇩🇪Bielefeld, NRW, Germany
Marienhospital Bottrop Klinik für Gynäkologie und Geburtshilfe / Gyn-Ambulanz
🇩🇪Bottrop, NRW, Germany
St. Elisabeth-Krankenhaus Hohenlind Brustzentrum
🇩🇪Cologne, NRW, Germany
Uniklinik Köln / Gebäude 70 Studienzentrale der Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe
🇩🇪Cologne, NRW, Germany
Kliniken der Stadt Köln / Krankenhaus Holweide Brustzentrum Holweide
🇩🇪Cologne, NRW, Germany
Klinikum Dortmund gGmbH Frauenklinik
🇩🇪Dortmund, NRW, Germany
Universitätsklinikum Düsseldorf Klinik für Frauenheilkunde & Geburtshilfe
🇩🇪Düsseldorf, NRW, Germany
Luisenkrankenhaus GmbH GynOnco Düsseldorf
🇩🇪Düsseldorf, NRW, Germany
Praxis Dr. Adhami
🇩🇪Erkelenz, NRW, Germany
St. Antonius Hospital Klinik für Hämatologie/Onkologie
🇩🇪Eschweiler, NRW, Germany
Universitätsklinikum Essen Klinik für Frauenheilkunde und Geburtshilfe
🇩🇪Essen, NRW, Germany
Kliniken Essen-Mitte, Klinik für Senologie/Interdisziplinäres Brustzentrum
🇩🇪Essen, NRW, Germany
Evangelische Kliniken Gelsenkirchen GmbH Klinik für Senologie
🇩🇪Gelsenkirchen, NRW, Germany
Wilhelm-Anton-Hospital Goch Klinik für Innere Medizin, Hämatologie u. Onkologie
🇩🇪Goch, NRW, Germany
Onkodok GmbH
🇩🇪Gütersloh, NRW, Germany
St. Barbara Klinik Brustzentrum
🇩🇪Hamm, NRW, Germany
Klinikum Leverkusen Medizinische Klinik 3
🇩🇪Leverkusen, NRW, Germany
Praxis für gynäkologische Onkologie am Ev. Krankenhaus Bethesda
🇩🇪Moenchengladbach, NRW, Germany
St. Franziskus-Hospital Brustzentrum
🇩🇪Münster, NRW, Germany
Universitätsklinikum Frauenheilkunde
🇩🇪Münster, NRW, Germany
ONCOLOGIANOVA Praxis Dr. Emde
🇩🇪Recklinghausen, NRW, Germany
Marienkrankenhaus Schwerte Brustzentrum
🇩🇪Schwerte, NRW, Germany
Marien-Krankenhaus Klinik für Gynäkologie und Geburtshilfe
🇩🇪Siegen, NRW, Germany
Diakonie Klinikum Jung Stilling Brustzentrum
🇩🇪Siegen, NRW, Germany
Praxisnetz Hämatologie / internistische Onkologie Praxis Troisdorf
🇩🇪Troisdorf, NRW, Germany
Christliches Klinikum Unna gGmbH Brustzentrum
🇩🇪Unna, NRW, Germany
Praxis für Hämatologie und internistische Onkologie Praxis Dr. Nusch
🇩🇪Velbert, NRW, Germany
Marien Hospital / Senologie Brustzentrum
🇩🇪Witten, NRW, Germany
Helios Universitätsklinikum Frauenheilkunde & Geburtshilfe
🇩🇪Wuppertal, NRW, Germany
Katholisches Klinikum Koblenz-Montabaur-Marienhof Koblenz Marienhof Koblenz - Gynäkologie
🇩🇪Koblenz, Rhineland-Palatinate, Germany
Klinikum Mutterhaus der Borromäerinnen Innere Medizin I / Onkologie
🇩🇪Trier, Rhineland-Palatinate, Germany
Universitätsklinikum des Saarlandes Frauenklinik
🇩🇪Homburg, Saarland, Germany
DRK Kliniken Saar / Krankenhaus Saarlouis Brustzentrum
🇩🇪Saarlouis, Saarland, Germany
Universitätsklinikum Halle Universitätsklinik für Gynäkologie
🇩🇪Halle / Saale, Saxony-Anhalt, Germany
Altmark-Klinikum Salzwedel Klinik für Frauenheilkunde
🇩🇪Salzwedel, Saxony-Anhalt, Germany
Johanniter Frauenklinik Stendal Gynäkologie
🇩🇪Stendal, Saxony-Anhalt, Germany
Klinikum Chemnitz Frauenklinik / Brustzentrum
🇩🇪Chemnitz, Saxony, Germany
Universitätsklinikum Dresden Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe
🇩🇪Dresden, Saxony, Germany
Universitätsklinikum Leipzig Gynäkologie und Universitäres Krebszentrum; Klinik und Poliklinik für Frauenheilkunde
🇩🇪Leipzig, Saxony, Germany
Kliniken St. Georg Klinik für Gynäkologie und Geburtshilfe
🇩🇪Leipzig, Saxony, Germany
Klinikum Obergöltzsch-Rodewisch Frauenklinik
🇩🇪Rodewisch, Saxony, Germany
Universitätsklinikum Schleswig-Holstein Campus Lübeck, Frauenklinik
🇩🇪Lübeck, Schleswig-Holstein, Germany
Universitätsklinikum Jena Klinik und Poliklinik für Frauenheilkunde und Fortpflanzungsmedizin
🇩🇪Jena, Thuringia, Germany
MVZ Nordhausen Praxis Dr. Andrea Grafe
🇩🇪Nordhausen, Thuringia, Germany
Charité Berlin, Klinik für Gynäkologie m.S. Senologie Brustzentrum (CCM)
🇩🇪Berlin, Germany
St. Gertrauden Krankenhaus Brustzentrum City Berlin
🇩🇪Berlin, Germany
Vivantes Klinikum Am Urban Brustzentrum
🇩🇪Berlin, Germany
DRK Klinikum Berlin-Köpenick Brustzentrum
🇩🇪Berlin, Germany
Evangelisches Waldkrankenhaus Spandau Klinik für Gynäkologie und Geburtshilfe
🇩🇪Berlin, Germany
Hämatologisch/Onkologische Schwerpunktpraxis Praxis Dr. Schreiber
🇩🇪Bremen, Germany
UKE Hamburg / Frauenklinik Brustzentrum am UKE
🇩🇪Hamburg, Germany
Agaplesion Diakonieklinikum Hamburg Frauenklinik, Brustzentrum u. Gyn. Tumorzentrum / Gyn. Studienambulanz
🇩🇪Hamburg, Germany
Mammazentrum Hamburg am Krankenhaus Jerusalem
🇩🇪Hamburg, Germany