Clinical trial NCT04055493: Adj. Marker-adjusted Personalized Therapy Comparing ET+Ribociclib vs Chemotherapy in Intermediate Risk, HR+/HER2- EBC
Official title: Adjuvant Dynamic Marker - Adjusted Personalized Therapy Comparing Endocrine Therapy Plus Ribociclib Versus Chemotherapy in Intermediate Risk, HR+/HER2- Early Breast Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Breast Cancer Female
Keywords: early breast cancer
ADAPT
endocrine therapy
ribociclib
intermediate risk
HER2 negative
HR positive
Lead sponsor: West German Study Group
Sponsor class: OTHER
Collaborators: name: Novartis
name: Genomic Health®, Inc.
First posted: 2019-08-13
Enrollment: 1684
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter, interventional, prospective, two-arm, randomized, open-label, controlled (neo)adjuvant, phase-III trial evaluating the efficacy and safety of ribociclib combined with endocrine therapy (ET) versus standard-of-care chemotherapy in early breast cancer (EBC) patients with molecular HR+/HER2- subtype.
Primary purpose: TREATMENT

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).

Eligibility criteria: Inclusion Criteria:

Patients eligible for inclusion in this study have to meet all of the following criteria:

A. Prior to REGISTRATION in the study:

1. 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

* patient underwent bilateral oophorectomy, or
* age ≥ 60, or
* 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:
* confirmed negative serum pregnancy test (β-hCG) before starting study treatment, or
* 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.

  6. Patient has HER2-negative breast cancer defined as
* a negative in-situ hybridization test or an IHC status of 0, 1+, or 2+,
* 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).

  7. 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).

9. 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):

1. cT2-4
2. c/pN positive
3. 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.

11. 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:

* absolute neutrophil count ≥ 1.5 × 109/L,
* platelets ≥ 100 × 109/L,
* hemoglobin ≥ 9.0 g/dL,
* estimated glomerular filtration rate (eGFR) ≥ 30 mL/min by a Cockcroft-Gault formula,
* INR ≤ 1.5,
* serum creatinine \< 1.5 mg/dL,
* 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,
* aspartate transaminase (AST) \< 2.5 × ULN,
* alanine transaminase (ALT) \< 2.5 × ULN. 14. 2-lead-ECG (CANKADO) with:
* QTcF interval at screening \< 450 msec (using Fridericia's correction),
* mean resting heart rate 50-90 bpm (determined from the ECG). 15. Ability to swallow ribociclib tablets or to administer other study medication, respectively.

  16. Ability to communicate with the investigator and comply with study procedures.

  17. Willing to remain during therapy at the clinical site, as required by the protocol.

Exclusion Criteria:

Patients eligible for inclusion in this study must not meet any of the following criteria:

1. Patient with distant metastases of breast cancer beyond regional lymph nodes.
2. Patient has received prior (neo)-adjuvant treatment with chemotherapy, ET, or any CDK4/6 inhibitor for breast cancer.
3. 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.
4. 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.
5. Patient with a known hypersensitivity to any of the excipients of ribociclib, ET, or standard-of-care chemotherapy.
6. Patient with inflammatory breast cancer at screening.
7. Patient is concurrently using other anti-cancer therapy.
8. Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.
9. Patient is currently receiving warfarin or other coumarin-derived anti-coagulant for treatment, prophylaxis, or otherwise.
10. Patient has not recovered from clinical and laboratory acute toxicities related to prior anticancer therapies to NCI CTCAE version 5.0 Grade ≤ 1.
11. Patient has a concurrent malignancy, or malignancy within 5 years of randomization, or known history of invasive breast cancer.
12. 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).
13. Patient has a known history of HIV infection.
14. Patient has known active hepatitis-B-virus (HBV) or hepatitis-C-virus (HCV) infection.
15. 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.).
16. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:

    * history of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry,
    * documented cardiomyopathy,
    * left ventricular ejection fraction (LVEF) \< 50 % as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO),
    * 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.
17. 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.
18. 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.
19. Participation in a prior investigational study within 30 days prior to enrollment or within five half-lives of the investigational product, whichever is longer.
20. Not able to understand and to comply with study instructions and requirements.
21. Pregnant or nursing (lactating) woman.
22. 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).
23. Use of oral (estrogen and progesterone), transdermal, injected, or implanted hormonal methods of contraception as well as hormonal replacement therapy.

Primary outcomes:
measure: invasive disease-free survival (iDFS)
timeFrame: at end of study, on average 5 years after start of treatment
measure: distant disease-free survival (dDFS)
timeFrame: at end of study, on average 5 years after start of treatment
Secondary outcomes:
measure: overall survival (OS) 95 % CI
timeFrame: at end of study, on average 5 years after start of treatment
measure: distant disease-free survival (dDFS) 95 % CI
timeFrame: at end of study, on average 5 years after start of treatment
measure: QoL
timeFrame: at end of study, on average 5 years after start of treatment
measure: treatment adherence
timeFrame: at end of study, on average 5 years after start of treatment
measure: pathological complete response (pCR)
timeFrame: at end of study, on average 5 years after start of treatment
measure: clinical response rate
timeFrame: at end of study, on average 5 years after start of treatment
measure: rate of breast-conservation therapy
timeFrame: at end of study, on average 5 years after start of treatment
Other outcomes:
Locations:
city: Aalen
country: Germany
facility: Ost-Alb Klinikum Brustzentrum
state: Baden-Württemberg
city: Baden-Baden
country: Germany
facility: Stadtklinik Baden-Baden Brustzentrum
state: Baden-Württemberg
city: Böblingen
country: Germany
facility: Kreiskliniken Böblingen Klinikum Böblingen Frauenklinik
state: Baden-Württemberg
city: Freiburg
country: Germany
facility: Uniklinikum Freiburg Frauenklinik
state: Baden-Württemberg
city: Freiburg
country: Germany
facility: Praxis für interdisziplinäre Onkologie & Hämatologie GbR Praxis am Diakonieklinikum
state: Baden-Württemberg
city: Heilbronn
country: Germany
facility: SLK-Kliniken-Heilbronn Frauenklinik
state: Baden-Württemberg
city: Ludwigsburg
country: Germany
facility: Klinikum Ludwigsburg Klinik für Frauenheilkunde u. Geburtshilfe
state: Baden-Württemberg
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen Universitäts-Frauenklinik
state: Baden-Württemberg
city: Ulm
country: Germany
facility: Universitätsfrauenklinik Ulm Frauenheilkunde und Geburtshilfe
state: Baden-Württemberg
city: Weinheim
country: Germany
facility: GRN Klinik Weinheim Gynäkologie
state: Baden-Württemberg
city: Munich
country: Germany
facility: Klinikum der Universität München Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Brustzentrum
state: Bavaria
city: München
country: Germany
facility: Rotkreuzkliniken München Frauenklinik - Gynäkologie
state: Bavaria
city: Würzburg
country: Germany
facility: Frauenklinik und Poliklinik / Studienzentrale Josef-Schneider-Straße 4
state: Bavaria
city: Cottbus
country: Germany
facility: Carl-Thiem-Klinikum / Brustzentrum Senologie der Frauenklinik
state: Brandenburg
city: Fürstenwalde
country: Germany
facility: Schwerpunktpraxis Gynäkologische Onkologie Praxis Dr. Heinrich
state: Brandenburg
city: Potsdam
country: Germany
facility: Klinikum Ernst von Bergmann Klinik für Gynäkologie und Geburtshilfe
state: Brandenburg
city: Bremerhaven
country: Germany
facility: Klinikum Bremerhaven Reinkenheide Frauenklinik
state: Bremen
city: Frankfurt am Main
country: Germany
facility: Klinikum Frankfurt Höchst Klinik für Gynäkologie und Geburtshilfe
state: Hesse
city: Frankfurt
country: Germany
facility: AGAPLESION Markus Krankenhaus / Brustzentrum Gynäkologie und Geburtshilfe
state: Hesse
city: Kassel
country: Germany
facility: Klinikum Kassel Frauenklinik
state: Hesse
city: Offenbach
country: Germany
facility: Sana Klinikum Klinik für Gynäkologie und Geburtshilfe, Studienambulanz AOZ
state: Hesse
city: Wiesbaden
country: Germany
facility: St. Josefs-Hospital Wiesbaden Frauenklinik - Gynäkologie
state: Hesse
city: Braunschweig
country: Germany
facility: Frauenärzte Casparistraße Studien GbR BS
state: Lower Saxony
city: Georgsmarienhütte
country: Germany
facility: MVZ II der Niels Stensen Kliniken Onkologie u. Hämatologie, Brustzenzrum
state: Lower Saxony
city: Hannover
country: Germany
facility: Medizinische Hochschulle Hannover Klinik für Frauenheilkunde und Geburtshilfe
state: Lower Saxony
city: Hannover
country: Germany
facility: DIAKOVERE Henriettenstift Frauenklinik
state: Lower Saxony
city: Hildesheim
country: Germany
facility: Gynäkologische Gemeinschaftspraxis-Ärztehaus am Bahnhofsplatz Klinische Studien
state: Lower Saxony
city: Lüneburg
country: Germany
facility: Städtisches Klinikum Lüneburg Frauenklinik
state: Lower Saxony
city: Stade
country: Germany
facility: MVZ Klinik Dr. Hancken Haematologie/Onkologie
state: Lower Saxony
city: Rostock
country: Germany
facility: UFK Klinikum Südstadt Frauenklinik
state: Mecklenburg-Vorpommern
city: Aachen
country: Germany
facility: Marienhospital Studienzentrale BrustCentrum Aachen-Kreis Heinsberg
state: NRW
city: Aachen
country: Germany
facility: Universitätsklinikum Aachen, Frauenklinik - Senologie
state: NRW
city: Bergisch-Gladbach
country: Germany
facility: EVK Bergisch Gladbach Brustzentrum
state: NRW
city: Bielefeld
country: Germany
facility: Onkologische Schwerpunktpraxis Bielefeld Praxis Dr. Just
state: NRW
city: Bottrop
country: Germany
facility: Marienhospital Bottrop Klinik für Gynäkologie und Geburtshilfe / Gyn-Ambulanz
state: NRW
city: Cologne
country: Germany
facility: St. Elisabeth-Krankenhaus Hohenlind Brustzentrum
state: NRW
city: Cologne
country: Germany
facility: Uniklinik Köln / Gebäude 70 Studienzentrale der Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe
state: NRW
city: Cologne
country: Germany
facility: Kliniken der Stadt Köln / Krankenhaus Holweide Brustzentrum Holweide
state: NRW
city: Dortmund
country: Germany
facility: Klinikum Dortmund gGmbH Frauenklinik
state: NRW
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf Klinik für Frauenheilkunde & Geburtshilfe
state: NRW
city: Düsseldorf
country: Germany
facility: Luisenkrankenhaus GmbH GynOnco Düsseldorf
state: NRW
city: Erkelenz
country: Germany
facility: Praxis Dr. Adhami
state: NRW
city: Eschweiler
country: Germany
facility: St. Antonius Hospital Klinik für Hämatologie/Onkologie
state: NRW
city: Essen
country: Germany
facility: Universitätsklinikum Essen Klinik für Frauenheilkunde und Geburtshilfe
state: NRW
city: Essen
country: Germany
facility: Kliniken Essen-Mitte, Klinik für Senologie/Interdisziplinäres Brustzentrum
state: NRW
city: Gelsenkirchen
country: Germany
facility: Evangelische Kliniken Gelsenkirchen GmbH Klinik für Senologie
state: NRW
city: Goch
country: Germany
facility: Wilhelm-Anton-Hospital Goch Klinik für Innere Medizin, Hämatologie u. Onkologie
state: NRW
city: Gütersloh
country: Germany
facility: Onkodok GmbH
state: NRW
city: Hamm
country: Germany
facility: St. Barbara Klinik Brustzentrum
state: NRW
city: Leverkusen
country: Germany
facility: Klinikum Leverkusen Medizinische Klinik 3
state: NRW
city: Moenchengladbach
country: Germany
facility: Praxis für gynäkologische Onkologie am Ev. Krankenhaus Bethesda
state: NRW
city: Münster
country: Germany
facility: St. Franziskus-Hospital Brustzentrum
state: NRW
city: Münster
country: Germany
facility: Universitätsklinikum Frauenheilkunde
state: NRW
city: Recklinghausen
country: Germany
facility: ONCOLOGIANOVA Praxis Dr. Emde
state: NRW
city: Schwerte
country: Germany
facility: Marienkrankenhaus Schwerte Brustzentrum
state: NRW
city: Siegen
country: Germany
facility: Marien-Krankenhaus Klinik für Gynäkologie und Geburtshilfe
state: NRW
city: Siegen
country: Germany
facility: Diakonie Klinikum Jung Stilling Brustzentrum
state: NRW
city: Troisdorf
country: Germany
facility: Praxisnetz Hämatologie / internistische Onkologie Praxis Troisdorf
state: NRW
city: Unna
country: Germany
facility: Christliches Klinikum Unna gGmbH Brustzentrum
state: NRW
city: Velbert
country: Germany
facility: Praxis für Hämatologie und internistische Onkologie Praxis Dr. Nusch
state: NRW
city: Witten
country: Germany
facility: Marien Hospital / Senologie Brustzentrum
state: NRW
city: Wuppertal
country: Germany
facility: Helios Universitätsklinikum Frauenheilkunde & Geburtshilfe
state: NRW
city: Koblenz
country: Germany
facility: Katholisches Klinikum Koblenz-Montabaur-Marienhof Koblenz Marienhof Koblenz - Gynäkologie
state: Rhineland-Palatinate
city: Trier
country: Germany
facility: Klinikum Mutterhaus der Borromäerinnen Innere Medizin I / Onkologie
state: Rhineland-Palatinate
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes Frauenklinik
state: Saarland
city: Saarlouis
country: Germany
facility: DRK Kliniken Saar / Krankenhaus Saarlouis Brustzentrum
state: Saarland
city: Halle / Saale
country: Germany
facility: Universitätsklinikum Halle Universitätsklinik für Gynäkologie
state: Saxony-Anhalt
city: Salzwedel
country: Germany
facility: Altmark-Klinikum Salzwedel Klinik für Frauenheilkunde
state: Saxony-Anhalt
city: Stendal
country: Germany
facility: Johanniter Frauenklinik Stendal Gynäkologie
state: Saxony-Anhalt
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz Frauenklinik / Brustzentrum
state: Saxony
city: Dresden
country: Germany
facility: Universitätsklinikum Dresden Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe
state: Saxony
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig Gynäkologie und Universitäres Krebszentrum; Klinik und Poliklinik für Frauenheilkunde
state: Saxony
city: Leipzig
country: Germany
facility: Kliniken St. Georg Klinik für Gynäkologie und Geburtshilfe
state: Saxony
city: Rodewisch
country: Germany
facility: Klinikum Obergöltzsch-Rodewisch Frauenklinik
state: Saxony
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein Campus Lübeck, Frauenklinik
state: Schleswig-Holstein
city: Jena
country: Germany
facility: Universitätsklinikum Jena Klinik und Poliklinik für Frauenheilkunde und Fortpflanzungsmedizin
state: Thuringia
city: Nordhausen
country: Germany
facility: MVZ Nordhausen Praxis Dr. Andrea Grafe
state: Thuringia
city: Berlin
country: Germany
facility: Charité Berlin, Klinik für Gynäkologie m.S. Senologie Brustzentrum (CCM)
city: Berlin
country: Germany
facility: St. Gertrauden Krankenhaus Brustzentrum City Berlin
city: Berlin
country: Germany
facility: Vivantes Klinikum Am Urban Brustzentrum
city: Berlin
country: Germany
facility: DRK Klinikum Berlin-Köpenick Brustzentrum
city: Berlin
country: Germany
facility: Evangelisches Waldkrankenhaus Spandau Klinik für Gynäkologie und Geburtshilfe
city: Bremen
country: Germany
facility: Hämatologisch/Onkologische Schwerpunktpraxis Praxis Dr. Schreiber
city: Hamburg
country: Germany
facility: UKE Hamburg / Frauenklinik Brustzentrum am UKE
city: Hamburg
country: Germany
facility: Agaplesion Diakonieklinikum Hamburg Frauenklinik, Brustzentrum u. Gyn. Tumorzentrum / Gyn. Studienambulanz
city: Hamburg
country: Germany
facility: Mammazentrum Hamburg am Krankenhaus Jerusalem
Study officials:
affiliation: Ludwigs-Maximilians-University Munich, Breast Cancer Centre
name: Nadia Harbeck, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: