Adjuvant Dynamic marker - Adjusted Personalized Therapy comparing endocrine therapy plus ribociclib versus chemotherapy in intermediate-risk, HR+/HER2- early breast cancer (ADAPTcycle)

Phase 3

Active, not recruiting

Conditions: HR+/HER2- early breast cancer

Registration Number: 2024-515769-32-00

Lead Sponsor: WSG Westdeutsche Studiengruppe GmbH

Brief Summary: To demonstrate

- superiority in invasive disease-free survival (iDFS) of ribociclib + ET vs. standard-of-care chemotherapy,

- survival rate >92 % in 5-years´ distant disease-free survival (dDFS) in the ribociclib + ET-group.

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: Ongoing, recruitment ended

Sex: Female

Target Recruitment: 1684

Inclusion Criteria

Written informed consent prior to any screening procedures.

Patient is classified as intermediate risk according to the ADAPT intermediate to high-risk definition (i) (as follows), or (only in case of missing Oncotype DX® data), according to the clinical intermediate-risk definition (ii) (as follows). (For detailed information see study protocol)

No contraindication for (neo)-adjuvant ET and/or chemotherapy

Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

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, haemoglobin ≥ 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.

12-lead-ECG with: QTcF interval at screening < 450 msec (using Fridericia’s correction), mean resting heart rate 50-90 bpm (determined from the ECG).

Ability to swallow ribociclib tablets or to administer other study medication, respectively.

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

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

Female.

≥ 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 oestradiol in the postmenopausal range per local normal range. 4b. OR: Pre-menopausal patients: confirmed negative serum or urine pregnancy test (β-hCG) before starting study treatment, or patient has had a hysterectomy.

Histologically confirmed diagnosis of primary oestrogen-receptor positive and/or progesterone-receptor positive (≥ 1%) early breast cancer by local laboratory.

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 analysed 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. Radiotherapy may be performed in parallel or sequentially to either ribociclib or standard of care treatment, as per investigator´s decision.

No evidence of distant metastasis (confirmed prior to randomization by CT thorax / abdomen, X-ray chest, ultrasound liver, bone scan, or PET-CT, respectively).

Patient has available tumour tissue from primary diagnostic biopsy.

Exclusion Criteria

Patient with distant metastases of breast cancer beyond regional lymph nodes.

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.

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.

Patient with a known hypersensitivity to any of the excipients of ribociclib, ET, or standard-of-care chemotherapy.

Patient with inflammatory breast cancer at screening.

Patient is concurrently using other anti-cancer therapy.

Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.

Patient is currently receiving warfarin or other coumarin-derived anti-coagulant for treatment, prophylaxis, or otherwise.

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.

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.

Participation in another investigational study in which the patient´s IMP-treatment is not yet completed and up to 30 days after ending of IMP-treatment in this respective investigational study

Patient has not recovered from clinical and laboratory acute toxicities related to prior anticancer therapies to NCI CTCAE version 5.0 Grade ≤ 1.

Not able to understand and to comply with study instructions and requirements.

Pregnant or nursing (lactating) woman.

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).

Use of oral (oestrogen and progesterone), transdermal, injected, or implanted hormonal methods of contraception as well as hormonal replacement therapy.

Patient has a concurrent malignancy, or malignancy within 5 years prior to randomization, or known history of invasive breast cancer.

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, diarrhoea, malabsorption syndrome, or small-bowel resection).

Patient has a known history of HIV infection. Screening for HIV- infection and testing for HIV is highly recommended according to current valid (local) clinical guidelines, but neither part of the interventional study procedures, nor required for enrolment.

Patient has known active hepatitis-B-virus (HBV) or hepatitis-C- virus (HCV) infection. Screening for HBV or HBC-infection and testing for hepatitis-B or -C is highly recommended according to current valid (local) clinical guidelines, but neither part of the interventional study procedures, nor required for enrollment.

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.).

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, polymorphic ventricular tachycardia in patients with long QT syndrome) including uncorrected hypokalaemia 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., bi-fascicular block, Mobitz type II, and 3rd-degree AV block), systolic blood pressure (SBP) > 160 or < 90 mmHg.

Patient has received prior (neo)-adjuvant treatment with chemotherapy, ET, or any CDK4/6 inhibitor for breast cancer.

Study & Design

Study Type: INTERVENTIONAL

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
iDFS and dDFS		iDFS and dDFS

Secondary Outcome Measures

Name	Time	Method
Pathological response rate (defined as ypT0/is/ypN0), as well as further definitions (ypT0/ypN0; ypT0/is/any ypN, near pCR (ypT1a/any ypN)),		Pathological response rate (defined as ypT0/is/ypN0), as well as further definitions (ypT0/ypN0; ypT0/is/any ypN, near pCR (ypT1a/any ypN)),
Overall survival (OS) and dDFS,		Overall survival (OS) and dDFS,
quality of life (QoL)		quality of life (QoL)
treatment adherence (measured by drug intake),		treatment adherence (measured by drug intake),
local and central Ki-67 values in all tissue samples.		local and central Ki-67 values in all tissue samples.
Clinical response rate (by palpation, ultrasound, and further methods),		Clinical response rate (by palpation, ultrasound, and further methods),
Rate of breast-conservation therapy		Rate of breast-conservation therapy

Trial Locations

Locations (89): Diakonie in Suedwestfalen gGmbH
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Siegen, Germany
Klinikum Mutterhaus der Borromaeerinnen gGmbH
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Trier, Germany
DRK Kliniken Berlin
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Berlin, Germany
GRN Gesundheitszentren Rhein-Neckar gGmbH
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Weinheim, Germany
Klinikum Leverkusen gGmbH
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Leverkusen, Germany
Medical Center - University Of Freiburg
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Freiburg Im Breisgau, Germany
St. Josefs-Hospital Wiesbaden GmbH
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Wiesbaden, Germany
Agaplesion Diakonieklinikum Hamburg gGmbH
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Hamburg, Germany
Marien-Hospital Witten
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Witten, Germany
Suedharz Klinikum Nordhausen gGmbH
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Nordhausen, Germany
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Diakonie in Suedwestfalen gGmbH
🇩🇪Siegen, Germany
Volker Mueller
Site contact
00492713334266
frauenklinik.jsk@diakonie-sw.de