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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

WSG Westdeutsche Studiengruppe GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 Jul 2019 → ongoing

Decision date (initial)

2024-10-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Exact Sciences · Novartis · Genomic Health

External identifiers

EU CT number

2024-515769-32-00

EudraCT number

2018-003749-40

ClinicalTrials.gov

NCT04055493

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

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.

Secondary objectives 9

1. overall survival (OS) and dDFS in both arms
2. differences in overall survival (OS) and dDFS
3. subgroup and multivariable survival analyses defined by key clinical, genomic, and endocrine-response parameters
4. quality of life (QoL) and correlation to treatment related symptoms measured by EQ-VAS and triggered symptom questionnaire
5. analysis of treatment adherence
6. comparison of Ki-67 values measured by any local pathologist vs. central pathologist in all tissue samples
7. to compare pCR by treatment arm
8. to compare clinical response rate by treatment arm
9. to compare prevalence of breast conservation therapy vs. mastectomy by treatment arm

Conditions and MedDRA coding

HR+/HER2- early breast cancer

Study design 4 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Written informed consent prior to any screening procedures.
2. Female.
3. ≥ 18 years of age.
4. 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.
5. Histologically confirmed diagnosis of primary oestrogen-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 analysed 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. Radiotherapy may be performed in parallel or sequentially to either ribociclib or standard of care treatment, as per investigator´s decision.
8. No evidence of distant metastasis (confirmed prior to randomization by CT thorax / abdomen, X-ray chest, ultrasound liver, bone scan, or PET-CT, respectively).
9. Patient has available tumour tissue from primary diagnostic biopsy.
10. 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)
11. No contraindication for (neo)-adjuvant ET and/or chemotherapy
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, 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.
14. 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).
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 23

1. Patient with distant metastases of breast cancer beyond regional lymph nodes.
2. Patient has not recovered from clinical and laboratory acute toxicities related to prior anticancer therapies to NCI CTCAE version 5.0 Grade ≤ 1.
3. Patient has a concurrent malignancy, or malignancy within 5 years prior to randomization, or known history of invasive breast cancer.
4. 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).
5. 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.
6. 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.
7. 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.).
8. 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.
9. Patient has received prior (neo)-adjuvant treatment with chemotherapy, ET, or any CDK4/6 inhibitor for breast cancer.
10. 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.
11. 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.
12. Patient with a known hypersensitivity to any of the excipients of ribociclib, ET, or standard-of-care chemotherapy.
13. Patient with inflammatory breast cancer at screening.
14. Patient is concurrently using other anti-cancer therapy.
15. Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.
16. Patient is currently receiving warfarin or other coumarin-derived anti-coagulant for treatment, prophylaxis, or otherwise.
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 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
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 (oestrogen and progesterone), transdermal, injected, or implanted hormonal methods of contraception as well as hormonal replacement therapy.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. iDFS and dDFS

Secondary endpoints 7

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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

WSG Westdeutsche Studiengruppe GmbH

Sponsor organisation

WSG Westdeutsche Studiengruppe GmbH

Address

Fliethstrasse 112-114, Stadtmitte Stadtmitte

City

Moenchengladbach

Postcode

41061

Country

Germany

Scientific contact point

Organisation

WSG Westdeutsche Studiengruppe GmbH

Contact name

Medical Board

Public contact point

Organisation

WSG Westdeutsche Studiengruppe GmbH

Contact name

Project Management

Third parties 6

Locations

1 EU/EEA country · 85 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications