Clinical trial NCT04565054: Adjuvant Therapy With Abemaciclib + SOC ET vs. SOC ET in Clinical or Genomic High Risk, HR+/HER2- EBC
Official title: Adj. Dynamic Marker - Adjusted Personalized Therapy Comparing Abemaciclib Combined With Standard Adjuvant Endocrine Therapy Versus Standard Adjuvant Endocrine Therapy in (Clinical or Genomic) High Risk, HR+/HER2- EBC
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Breast Cancer Female
Keywords: early breast cancer
ADAPT
endocrine therapy
abemaciclib
high risk
HER2 negative
HR positive
Lead sponsor: West German Study Group
Sponsor class: OTHER
Collaborators: name: Eli Lilly and Company
name: Genomic Health®, Inc.
First posted: 2020-09-25
Enrollment: 1260
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 adjuvant, phase-III trial evaluating the efficacy and safety of abemaciclib with endocrine therapy (ET) versus standard-of-care endocrine therapy in early breast cancer (EBC) patients with molecular HR+/HER2- subtype.
Primary purpose: TREATMENT

Brief summary: Patients with breast cancer, who have completed first line therapy (e.g., radiotherapy, chemotherapy, surgery), and who have to be identified with having a high risk of recurrence of cancer, will be eligible for the study. This patient group is currently offered a standard of care chemotherapy plus endocrine therapy (ET). The study investigates whether the patient group with high-risk early breast cancer benefits from treatment with the medication abemaciclib in combination with ET compared to ET alone.

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 positive national and international feedback regarding the ADAPT-concept as a whole.

The aim of this ADAPTlate phase-III-trial is to gain further knowledge of the group of patients at intermediate to high risk for disease recurrence, who have completed definite locoregional therapy (with or without neoadjuvant or adjuvant chemotherapy). With ADAPTlate it is planned to investigate if the intermediate to high-risk patient group identified during the screening phase derives additional benefit from treatment with abemaciclib in combination with ET compared to ET alone.

Eligibility criteria: Inclusion Criteria:

A. Prior to REGISTRATION

1. Written informed consent prior to any study procedures (outcomes of standard-of-care procedures performed before signing of informed consent by the patient but within allowed screening period can be used for screening of patient). 2. Female. 3. ≥ 18 years of age. 4a. EITHER: (Post)menopausal status at the time of initiation of 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, or ovarian suppression) and/or FSH and estradiol in the postmenopausal range per local normal range.

  4b. OR: Pre-/perimenopausal patients:
* confirmed negative serum or urine pregnancy test (β-hCG) before starting study treatment, or
* patient has had a hysterectomy. 5. Histologically confirmed diagnosis(by local laboratory ) of estrogen-receptor positive and/or progesterone-receptor positive (\>1% ) primary early breast cancer or local relapse. In case the receptor status from local pathology is unclear a central pathology review is obligatory. Results must be known prior to randomization.

  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 analyzed tissue sample at initial diagnosis by a local laboratory).

  7. Patients are eligible
* with completed (i.e., 5 years according to SoC), planned or ongoing adjuvant endocrine therapy, without any signs of distant relapse or secondary malignancy AND
* if primary diagnosis was 6 years or less before enrollment 8a. Intermediate to high clinical or genomic risk, defined as either one of the following criteria:
* c or p or ypN 2-3 with/without (neo)adjuvant chemotherapy;
* in patients with c/ypN0-1:
* non-pCR in patients with G3 or c/ypN1
* high biological risk defined as G3 with Ki-67 ≥40%
* or high genomic risk (RS\>25 (known or Oncotype Dx® in screening phase) or another test)
* high CTS5 score or UICC stage IIb (clinical if neoadjuvant chemotherapy or pathological)

OR, if patients do not fulfill above criteria:

* patients ≤50 years old or pre-/perimenopausal and c or (y)pN1 disease (in particular if ET-non-response or no chemotherapy)
* patients \>50 years old and postmenopausal and c or (y)pN1 with intermediate genomic risk (RS≥18) or non-low risk by another test

ET non-response definition:

Ki-67 post-treatment \> 10% (central or local pathology value) OR 8b. Patients after isolated locoregional relapse with high-risk patterns (e.g., rpT2-3 or rpN1-3 or G3 or Ki-67 pre-treatment ≥20%), once surgery with free margins was completed Note: Inclusion is only possible for the first locoregional relapse removed by surgery (free margins) OR 8c. Patients with any high clinical risk at Investigator´s assessment but not fulfilling above criteria: consultation with sponsor required

B. Prior to RANDOMIZATION in the study 9. Completed primary therapy of breast cancer according to current guidelines, i.e., after (neo)adjuvant treatment, definite surgery and radiotherapy, if applicable.

10. No clinical evidence of distant metastasis (confirmation recommended prior to randomization by either combination of or either one of the following examinations: CT thorax / abdomen, chest X-ray, liver ultrasound, bone scan, PET-CT). 11. Patient has available tumor tissue from primary diagnostic biopsy. 12. No contraindication for adjuvant ET. 13. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 14. 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 ≥ 8.0 g/dL,
* total bilirubin ≤ 1.5 ULN, except for patients with Gilbert's Syndrome who may only be included if the total bilirubin is ≤ 2.0 × ULN or direct bilirubin within normal ranges,
* aspartate transaminase (AST) ≤ 3 × ULN,
* alanine transaminase (ALT) ≤ 3 × ULN,
* serum creatinine ≤ 1.5 x ULN. 15. Ability to swallow abemaciclib tablets or to administer other study medication, respectively.

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

  17. Willing to receive therapy by 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. Previously received CDK 4/6 inhibitor.
3. Patient with a known hypersensitivity to any of the excipients of abemaciclib or standard-of-care endocrine therapy.
4. Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.
5. Patient has not recovered from clinical and laboratory acute toxicities related to prior anticancer therapies to NCI CTCAE version 5.0 Grade ≤ 1 (polyneuropathy ≤ 2 is allowed).
6. Patient has a concurrent malignancy or non-breast malignancy within 5 years prior to randomization.
7. 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).
8. Patient has any active systemic bacterial infection (requiring intravenous antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C \[for example, hepatitis B surface antigen positive\]. Screening is not required for enrollment.
9. 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., interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment \[e.g. estimated creatinine clearance \<30ml/min\], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea, etc.).
10. Patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
11. Patient is currently receiving any of the following substances, which cannot be discontinued 7 days prior to day 1 of study treatment:

    o concomitant medications and herbal supplements, that are strong inducers or inhibitors of CYP3A4.
12. Participation in a prior investigational study within 30 days prior to enrollment.
13. Not able to understand and to comply with study instructions and requirements.
14. Pregnant or nursing (lactating) woman.
15. 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:

    1. total abstinence (when this is in line with the preferred and usual lifestyle of the patient).
    2. female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment.
    3. 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.
    4. placement of an intrauterine device (IUD).
    5. use of condom + spermicide.
16. 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, 3-6 years after start of study treatment
Secondary outcomes:
measure: overall survival (OS)
timeFrame: at end of study, 3-6 years after start of treatment
measure: differences in overall survival (OS) and dDFS
timeFrame: at end of study, 3-6 years after start of study treatment
measure: subgroup and multivariable survival analyses
timeFrame: at end of study, 3-6 years after start of study treatment
measure: CNS metastases
timeFrame: at end of study, 3-6 years after start of study treatment
measure: EORTC QLQ-C30
timeFrame: at end of study, on average 3-6 years after start of treatment
measure: EORTC QLQ-BR23
timeFrame: at end of study, on average 3-6 years after start of treatment
measure: EQ-5D-5L
timeFrame: at end of study, on average 3-6 years after start of treatment
Other outcomes:
Locations:
city: Freiburg
country: Germany
facility: Praxis für interdisziplinäre Onkologie & Hämatologie
state: Baden-Württemberg
city: Heilbronn
country: Germany
facility: SLK Kliniken Heilbronn Klinik für Gynäkologie und Geburtshilfe
state: Baden-Württemberg
city: Ravensburg
country: Germany
facility: Studienzentrum Onkologie Ravensburg Prof. Dr. Dechow, Prof. Dr. Decker, Dr. Nonnenbroich GbR
state: Baden-Württemberg
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm Frauenheilkunde, Geburtshilfe
state: Baden-Württemberg
city: Weinheim
country: Germany
facility: GRN-Klinik Weinheim Gynäkologie und Geburtshilfe
state: Baden-Württemberg
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen Department für Frauengesundheit, Brustzentrum
state: Baden-Wüttenburg
city: Augsburg
country: Germany
facility: Gemeinschaftspraxis Dr. Heinrich, Prof. Dr. Bangerter
state: Bavaria
city: Munich
country: Germany
facility: Medizinisches Zentrum für Hämatologie und Onkologie München MVZ GmbH
state: Bavaria
city: Würzburg
country: Germany
facility: Hämatologisch-Onkologische Schwerpunktpraxis Würzburg GbR Dr. Schöttker/ Dr. Pretscher
state: Bavaria
city: Muenchen
country: Germany
facility: Klinikum der Universität München Campus Großhadern Frauenheilunde und Geburtsklinik
state: Bayern
city: München
country: Germany
facility: Rotkreuzkliniken München, Interdisziplinbäres Brustzentrum
state: Bayern
city: Cottbus
country: Germany
facility: Medizinische Universität Lausitz - Carl-Thiem Frauenklinik
state: Brandenburg
city: Potsdam
country: Germany
facility: Klinikum Ernst von Bergmann gGmbH Brustzentrum
state: Brandenburg
city: Wiesbaden
country: Germany
facility: St. Josefs-Hospital Wiesbaden GmbH Ambulanz der Frauenklinik, Brustzentrum
state: Hessen
city: Frankfurt a.M.
country: Germany
facility: Onco Medical Consult GmbH
state: Hesse
city: Langen
country: Germany
facility: Gemeinschaftspraxis für Hämatologie und Onkologie
state: Hesse
city: Braunschweig
country: Germany
facility: Studien GbR Braunschweig Dr. Lorenz/Dr. Kreiss-Sender
state: Lower Saxony
city: Goslar
country: Germany
facility: ÜBAG MVZ Onkologische Kooperation Harz
state: Lower Saxony
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover Frauenheilkunde
state: Lower Saxony
city: Leer
country: Germany
facility: Onkologie UnterEms Leer-Emden-Papenburg Dr. L. Müller
state: Lower Saxony
city: Oldenburg
country: Germany
facility: Pius-Hospital Oldenburg Hämatologie, Onkologie
state: Lower Saxony
city: Rostock
country: Germany
facility: Klinikum Südstadt Rostock Frauenklinik
state: Mecklenburg-Vorpommern
city: Georgsmarienhütte
country: Germany
facility: MVZ II der Niels Stensen Kliniken Onkologie u. Hämatologie
state: Niedersachsen
city: Hannover
country: Germany
facility: Diakovere Henriettenstift Frauenklinik
state: Niedersachsen
city: Köln
country: Germany
facility: Kliniken der Stadt Köln Krankenhaus Köln-Holweide Medizinische Klinik Brustzentrum
state: Nordrhein-Westfalen
city: Aachen
country: Germany
facility: Marienhospital GmbH Studienzentrale Brustcentrum Aachen-Kreis Heinsberg
state: NRW
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen Gynäkologie und Geburtsmedizin
state: NRW
city: Bergisch Gladbach
country: Germany
facility: Evangelisches Krankenhaus Bergisch Gladbach gGmbH Brustzentrum,
state: NRW
city: Bielefeld
country: Germany
facility: Onkologische Schwerpunktpraxis Bielefeld
state: NRW
city: Bonn
country: Germany
facility: Gynäkologisches Zentrum Bonn PD Dr. med. Christian Kurbacher
state: NRW
city: Cologne
country: Germany
facility: GYNONOVA GbR Schwerpunktpraxis für gynäkologische Onkologie
state: NRW
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf Frauenheilkunde und Geburtshilfe
state: NRW
city: Düsseldorf
country: Germany
facility: Luisenkrankenhaus Brustzentrum
state: NRW
city: Eschweiler
country: Germany
facility: St.-Antonius-Hospital Eschweiler Hämatologie/Onkologie
state: NRW
city: Essen
country: Germany
facility: Kliniken Essen-Mitte, Klinik für Senologie/Interdisziplinäres Brustzentrum
state: NRW
city: Essen
country: Germany
facility: Universitätsklinikum Essen Frauenheilkunde und Geburtshilfe
state: NRW
city: Gütersloh
country: Germany
facility: Onkologische Schwerpunktpraxis
state: NRW
city: Hildesheim
country: Germany
facility: Praxisgemeinschaft Gynäkologische Onkologie & Spezielle Operative Gynäkologie
state: NRW
city: Krefeld
country: Germany
facility: Zentrum für ambulante gynäkologisch Onkologie - ZAGO Haus 03
state: NRW
city: Köln
country: Germany
facility: St. Elisabeth-Krankenhaus GmbH, Brustzentrum - Senologie
state: NRW
city: Lüneburg
country: Germany
facility: Städtisches Klinikum Lüneburg Frauenklinik
state: NRW
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden Innere Medizin, Hämatologie, Onkologie
state: NRW
city: Moenchengladbach
country: Germany
facility: Brustzentrum Niederrhein, im ev. Krankenhaus Bethesda
state: NRW
city: Münster
country: Germany
facility: Universitätsklinikum Münster Brustzentrum
state: NRW
city: Schwerte
country: Germany
facility: Marien Krankenhaus Schwerte MKS St. Paulus GmbH
state: NRW
city: Unna
country: Germany
facility: Christliches Klinikum Unna Mitte Gynäkologie und Geburtshilfe
state: NRW
city: Witten
country: Germany
facility: Marien Hospital Witten Brustzentrum
state: NRW
city: Wuppertal
country: Germany
facility: Helios Klinikum Wuppertal Landesfrauenklinik
state: NRW
city: Trier
country: Germany
facility: Klinikum Mutterhaus der Borromäerinnen Innere Medizin 1
state: Rheinland-Pfalz
city: Koblenz
country: Germany
facility: Praxisklinik für Hämatologie und Onkologie Koblenz
state: Rhineland-Palatinate
city: Homburg (Saar)
country: Germany
facility: Universitätsklinikum des Saarlandes Klinik für Frauenheilkunde
state: Saarland
city: Rodewisch
country: Germany
facility: Klinikum Obergöltzsch Brustzentrum Vogtland
state: Sachsen
city: Halle (Saale)
country: Germany
facility: Universitätsklinikum Halle (UKH), Universitätsklinik und Poliklinik für Gynäkologie
state: Saxony Anhalt
city: Magdeburg
country: Germany
facility: Klinikum Magdeburg Frauenheilkunde und Geburtshilfe
state: Saxony-Anhalt
city: Stendal
country: Germany
facility: Johanniter Krankenhaus Frauenklinik
state: Saxony-Anhalt
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz Frauenheilkunde und Geburtshilfe
state: Saxony
city: Dresden
country: Germany
facility: Onkozentrum Dresden/Freiberg
state: Saxony
city: Dresden
country: Germany
facility: Onkologische Gemeinschaftspraxis
state: Saxony
city: Leipzig
country: Germany
facility: Klinikum St. Georg Gynäkologie und Geburtshilfe
state: Saxony
city: Berlin
country: Germany
facility: MediOnko-Institut GbR
city: Berlin
country: Germany
facility: Praxis für gynäkologische Onkologie im Brustzentrum City am Sankt Gertrauden KH
city: Berlin
country: Germany
facility: DRK Kliniken Berlin Köpenick Brustzentrum im Onkozentrum
city: Bremen
country: Germany
facility: Onkologisch-Hämatologische Schwerpunktpraxis
city: Hamburg
country: Germany
facility: AGAPLESION Diakonie-Klinikum Hamburg Gyn. Studienambulanz
city: Hamburg
country: Germany
facility: Mammazentrum Hamburg MVZ GbR
city: Kassel
country: Germany
facility: Brustzentrum, Elisabeth-Krankenhaus gGmbH
city: Saarbrücken
country: Germany
facility: Caritas Traegergesellschaft Saarbruecken mbH (CTS) Frauenklinik
Study officials:
affiliation: Westdeutsche Studiengruppe GmbH
name: Oleg Gluz, PD Dr. med.
role: PRINCIPAL_INVESTIGATOR
References: