Adj. Marker-adjusted Personalized Therapy Comparing ET+Ribociclib vs Chemotherapy in Intermediate Risk, HR+/HER2- EBC

Breast Cancer Female Clinical Trial

— ADAPTcycle  

Official title:

Adjuvant Dynamic Marker - Adjusted Personalized Therapy Comparing Endocrine Therapy Plus Ribociclib Versus Chemotherapy in Intermediate Risk, HR+/HER2- Early Breast Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04055493
• Other study ID #: WSG-AM08
• Status: Recruiting
• Phase: Phase 3
• Start date: July 2, 2019
• Est. completion date: July 31, 2027

Study information

• Verified date: May 2023
• Source: West German Study Group
• Contact: Anja Braschoss, MD
• Phone: +49-176-82119153
• Email: anja.braschoss[@]wsg-online.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Recruiting
• Enrollment: 1670
• Est. completion date: July 31, 2027
• Est. primary completion date: July 31, 2027
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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 (ß-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.

Related Conditions & MeSH terms

• Breast Cancer Female
• Breast Neoplasms

Intervention

Drug:
• Ribociclib 200Mg Oral Tablet
3 x 200 MG per os

Locations

Country	Name	City	State
Germany	Marienhospital Praxis Dr. Danaei	Aachen	NRW
Germany	Marienhospital Studienzentrale - BrustCentrum Aachen Kreis Heinsberg	Aachen	NRW
Germany	Universitätsklinikum Aachen, Frauenklinik - Senologie	Aachen	NRW
Germany	Ost-Alb Klinikum Brustzentrum	Aalen	Baden-Württemberg
Germany	Stadtklinik Baden-Baden Brustzentrum	Baden-Baden	Baden-Württemberg
Germany	EVK Bergisch Gladbach Brustzentrum	Bergisch-Gladbach	NRW
Germany	Charité Berlin, Klinik für Gynäkologie m.S. Senologie Brustzentrum (CCM)	Berlin
Germany	DRK Klinikum Berlin-Köpenick Brustzentrum	Berlin
Germany	Evangelisches Waldkrankenhaus Spandau Klinik für Gynäkologie und Geburtshilfe	Berlin
Germany	St. Gertrauden Krankenhaus Brustzentrum City Berlin	Berlin
Germany	Vivantes Klinikum Am Urban Brustzentrum	Berlin
Germany	Onkologische Schwerpunktpraxis Bielefeld Praxis Dr. Just	Bielefeld	NRW
Germany	Kreiskliniken Böblingen Klinikum Böblingen Frauenklinik	Böblingen	Baden-Württemberg
Germany	Marienhospital Bottrop Klinik für Gynäkologie und Geburtshilfe / Gyn-Ambulanz	Bottrop	NRW
Germany	Frauenärzte Casparistraße Studien GbR BS	Braunschweig	Lower Saxony
Germany	Hämatologisch/Onkologische Schwerpunktpraxis Praxis Dr. Schreiber	Bremen
Germany	Klinikum Bremerhaven Reinkenheide Frauenklinik	Bremerhaven	Bremen
Germany	Klinikum Chemnitz Frauenklinik / Brustzentrum	Chemnitz	Saxony
Germany	Kliniken der Stadt Köln / Krankenhaus Holweide Brustzentrum Holweide	Cologne	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	Carl-Thiem-Klinikum / Brustzentrum Senologie der Frauenklinik	Cottbus	Brandenburg
Germany	Klinikum Dortmund gGmbH Frauenklinik	Dortmund	NRW
Germany	Universitätsklinikum Dresden Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe	Dresden	Saxony
Germany	Luisenkrankenhaus GmbH GynOnco Düsseldorf	Düsseldorf	NRW
Germany	Universitätsklinikum Düsseldorf Klinik für Frauenheilkunde & Geburtshilfe	Düsseldorf	NRW
Germany	Praxis Dr. Adhami	Erkelenz	NRW
Germany	Universitätsklinik Erlangen Frauenklinik	Erlangen	Bavaria
Germany	St. Antonius Hospital Klinik für Hämatologie/Onkologie	Eschweiler	NRW
Germany	Kliniken Essen-Mitte, Klinik für Senologie/Interdisziplinäres Brustzentrum	Essen	NRW
Germany	Universitätsklinikum Essen Klinik für Frauenheilkunde und Geburtshilfe	Essen	NRW
Germany	Klinikum Esslingen Klinikum für Frauenheilkunde und Geburtshilfe	Esslingen	Baden-Württemberg
Germany	AGAPLESION Markus Krankenhaus / Brustzentrum Gynäkologie und Geburtshilfe	Frankfurt	Hesse
Germany	Klinikum Frankfurt Höchst Klinik für Gynäkologie und Geburtshilfe	Frankfurt am Main	Hesse
Germany	Praxis für interdisziplinäre Onkologie & Hämatologie GbR Praxis am Diakonieklinikum	Freiburg	Baden-Württemberg
Germany	Uniklinikum Freiburg Frauenklinik	Freiburg	Baden-Württemberg
Germany	Schwerpunktpraxis Gynäkologische Onkologie Praxis Dr. Heinrich	Fürstenwalde	Brandenburg
Germany	Evangelische Kliniken Gelsenkirchen GmbH Klinik für Senologie	Gelsenkirchen	NRW
Germany	MVZ II der Niels Stensen Kliniken Onkologie u. Hämatologie, Brustzenzrum	Georgsmarienhütte	Lower Saxony
Germany	Wilhelm-Anton-Hospital Goch Klinik für Innere Medizin, Hämatologie u. Onkologie	Goch	NRW
Germany	Onkodok GmbH	Gütersloh	NRW
Germany	Universitätsklinikum Halle Universitätsklinik für Gynäkologie	Halle / Saale	Saxony-Anhalt
Germany	Agaplesion Diakonieklinikum Hamburg Frauenklinik, Brustzentrum u. Gyn. Tumorzentrum / Gyn. Studienambulanz	Hamburg
Germany	Mammazentrum Hamburg am Krankenhaus Jerusalem	Hamburg
Germany	UKE Hamburg / Frauenklinik Brustzentrum am UKE	Hamburg
Germany	St. Barbara Klinik Brustzentrum	Hamm	NRW
Germany	DIAKOVERE Henriettenstift Frauenklinik	Hannover	Lower Saxony
Germany	Medizinische Hochschulle Hannover Klinik für Frauenheilkunde und Geburtshilfe	Hannover	Lower Saxony
Germany	SLK-Kliniken-Heilbronn Frauenklinik	Heilbronn	Baden-Württemberg
Germany	Gynäkologische Gemeinschaftspraxis-Ärztehaus am Bahnhofsplatz Klinische Studien	Hildesheim	Lower Saxony
Germany	Universitätsklinikum des Saarlandes Frauenklinik	Homburg	Saarland
Germany	Universitätsklinikum Jena Klinik und Poliklinik für Frauenheilkunde und Fortpflanzungsmedizin	Jena	Thuringia
Germany	Klinikum Kassel Frauenklinik	Kassel	Hesse
Germany	Katholisches Klinikum Koblenz-Montabaur-Marienhof Koblenz Marienhof Koblenz - Gynäkologie	Koblenz	Rhineland-Palatinate
Germany	Praxisklinik für Hämatologie und Onkologie Institu für Versorgungsforschung in der Onkologie	Koblenz	Rhineland-Palatinate
Germany	Kliniken St. Georg Klinik für Gynäkologie und Geburtshilfe	Leipzig	Saxony
Germany	Universitätsklinikum Leipzig Gynäkologie und Universitäres Krebszentrum; Klinik und Poliklinik für Frauenheilkunde	Leipzig	Saxony
Germany	Klinikum Leverkusen Medizinische Klinik 3	Leverkusen	NRW
Germany	Universitätsklinikum Schleswig-Holstein Campus Lübeck, Frauenklinik	Lübeck	Schleswig-Holstein
Germany	Klinikum Ludwigsburg Klinik für Frauenheilkunde u. Geburtshilfe	Ludwigsburg	Baden-Württemberg
Germany	Städtisches Klinikum Lüneburg Frauenklinik	Lüneburg	Lower Saxony
Germany	Praxis für gynäkologische Onkologie am Ev. Krankenhaus Bethesda	Moenchengladbach	NRW
Germany	Rotkreuzkliniken München Frauenklinik - Gynäkologie	München	Bavaria
Germany	Klinikum der Universität München Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Brustzentrum	Munich	Bavaria
Germany	St. Franziskus-Hospital Brustzentrum	Münster	NRW
Germany	Universitätsklinikum Frauenheilkunde	Münster	NRW
Germany	MVZ Nordhausen Praxis Dr. Andrea Grafe	Nordhausen	Thuringia
Germany	Sana Klinikum Klinik für Gynäkologie und Geburtshilfe, Studienambulanz AOZ	Offenbach	Hesse
Germany	Klinikum Ernst von Bergmann Klinik für Gynäkologie und Geburtshilfe	Potsdam	Brandenburg
Germany	ONCOLOGIANOVA Praxis Dr. Emde	Recklinghausen	NRW
Germany	Klinikum Obergöltzsch-Rodewisch Frauenklinik	Rodewisch	Saxony
Germany	UFK Klinikum Südstadt Frauenklinik	Rostock	Mecklenburg-Vorpommern
Germany	DRK Kliniken Saar / Krankenhaus Saarlouis Brustzentrum	Saarlouis	Saarland
Germany	Altmark-Klinikum Salzwedel Klinik für Frauenheilkunde	Salzwedel	Saxony-Anhalt
Germany	Marienkrankenhaus Schwerte Brustzentrum	Schwerte	NRW
Germany	Diakonie Klinikum Jung Stilling Brustzentrum	Siegen	NRW
Germany	Marien-Krankenhaus Klinik für Gynäkologie und Geburtshilfe	Siegen	NRW
Germany	MVZ Klinik Dr. Hancken Haematologie/Onkologie	Stade	Lower Saxony
Germany	Johanniter Frauenklinik Stendal Gynäkologie	Stendal	Saxony-Anhalt
Germany	Klinikum Mutterhaus der Borromäerinnen Innere Medizin I / Onkologie	Trier	Rhineland-Palatinate
Germany	Praxisnetz Hämatologie / internistische Onkologie Praxis Troisdorf	Troisdorf	NRW
Germany	Universitätsklinikum Tübingen Universitäts-Frauenklinik	Tübingen	Baden-Württemberg
Germany	Universitätsfrauenklinik Ulm Frauenheilkunde und Geburtshilfe	Ulm	Baden-Württemberg
Germany	Christliches Klinikum Unna gGmbH Brustzentrum	Unna	NRW
Germany	Praxis für Hämatologie und internistische Onkologie Praxis Dr. Nusch	Velbert	NRW
Germany	GRN Klinik Weinheim Gynäkologie	Weinheim	Baden-Württemberg
Germany	St. Josefs-Hospital Wiesbaden Frauenklinik - Gynäkologie	Wiesbaden	Hesse
Germany	Marien Hospital / Senologie Brustzentrum	Witten	NRW
Germany	Helios Universitätsklinikum Frauenheilkunde & Geburtshilfe	Wuppertal	NRW
Germany	Frauenklinik und Poliklinik / Studienzentrale Josef-Schneider-Straße 4	Würzburg	Bavaria

Sponsors (3)

Lead Sponsor	Collaborator
West German Study Group	Genomic Health®, Inc., Novartis

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	invasive disease-free survival (iDFS)	superiority in invasive disease-free survival (iDFS) of ribociclib + ET vs. standard-of-care chemotherapy	at end of study, on average 5 years after start of treatment
Primary	distant disease-free survival (dDFS)	distant disease-free survival (dDFS) in the ribociclib + ET-group to demonstrate survival rate >92%	at end of study, on average 5 years after start of treatment
Secondary	overall survival (OS) 95 % CI	95 %-confidence interval (CI) for OS in both arms	at end of study, on average 5 years after start of treatment
Secondary	distant disease-free survival (dDFS) 95 % CI	95 %-confidence interval (CI) for dDFS in both arms	at end of study, on average 5 years after start of treatment
Secondary	QoL	quality of life (QoL) and correlation to treatment-related symptoms measured by EQ-VAS and triggered symptom questionnaire,	at end of study, on average 5 years after start of treatment
Secondary	treatment adherence	treatment adherence measured by drug intake compared between treatment arms	at end of study, on average 5 years after start of treatment
Secondary	pathological complete response (pCR)	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	at end of study, on average 5 years after start of treatment
Secondary	clinical response rate	clinical response rate (by palpation, ultrasound, and further methods) compared between treatment arms	at end of study, on average 5 years after start of treatment
Secondary	rate of breast-conservation therapy	prevalence of breast conservation therapy vs. mastectomy compared between treatment arms	at end of study, on average 5 years after start of treatment