A phase III multi-center, randomized, open-label trial to evaluate efficacy and safety of ribociclib with endocrine therapy as adjuvant treatment in patients with HR+/HER2- Early Breast Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 May 2019 → ongoing

Decision date (initial)

2024-07-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Novartis Pharma AG with OMS ID: ORG-100003908

External identifiers

EU CT number

2023-510357-42-00

EudraCT number

2018-002998-21

ClinicalTrials.gov

NCT03701334

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others, Pharmacokinetic, Efficacy

To compare iDFS for ribociclib + ET versus ET in patients with HR-positive,
HER2-negative, EBC

Secondary objectives 6

1. To evaluate the two treatment arms with respect to recurrence-free survival (RFS)
2. To evaluate the two treatment arms with respect to distant disease free survival (DDFS)
3. To evaluate the two treatment arms with respect to overall survival (OS)
4. To evaluate patient reported outcomes (PRO) for health-related quality of life (QoL) in the two treatment arms
5. To evaluate safety and tolerability of the treatment regimen
6. To characterize the pharmacokinetics (PK) of ribociclib when given in combination with NSAI (and goserelin if applicable)

Conditions and MedDRA coding

hormone receptor (HR)-positive, HER2-negative, early breast cancer (EBC).

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. Signed and dated Patient Informed Consent Form (PICF) obtained prior to any trial-specific screening procedure.
2. Patient is ≥ 18 years-old at the time of PICF signature.
3. Patient is female with known menopausal status at the time of randomization or initiation of adjuvant ET (whichever occurs earlier), or male. Postmenopausal status is defined as: • Patient underwent bilateral oophorectomy, or • Age ≥ 60 years, or • Age < 60 years and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression) and Follicle-stimulating hormone (FSH) and plasma estradiol are in the postmenopausal ranges per local normal ranges. • If taking tamoxifen or toremifene and age <60 years, then FSH and plasma estradiol level in postmenopausal ranges.
4. Patient with histologically confirmed unilateral primary invasive adenocarcinoma of the breast with a date of initial cytologic or histologic diagnosis (i.e. date of the pathology report that confirmed the BC diagnosis) within 18 months prior to randomization. Patient with a multicentric and/or multifocal tumor is eligible if all histopathologically examined lesions meet the pathologic criteria in inclusion criteria 5 and 6.
5. Patient has breast cancer that is positive for ER and/or PgR according to the local laboratory as determined on the most recently analyzed tissue sample
6. Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0 or 1+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required to confirm the HER2-negative status (based on the most recently analyzed tissue sample tested by a local laboratory)
7. Patient (except those enrolled in China) has available archival tumor tissue from the surgical specimen, for submission to a central laboratory
8. Patient, after surgical resection where tumor was removed completely, with the final surgical specimen microscopic margins free from tumor, and belongs to one of the following categories:  Anatomic Stage Group III, or  Anatomic Stage Group IIB, or  Anatomic Stage Group IIA that is either: • N1, or • N0, with: • Grade 3, or • Grade 2, with any of the following criteria: • Ki67 ≥ 20%, or • Oncotype DX Breast Recurrence Score ≥ 26, or • Prosigna/PAM50 categorized as high risk, or • MammaPrint categorized as high risk, or • EndoPredict EPclin Risk Score categorized as high risk
9. If indicated, patient has completed adjuvant and/or neoadjuvant chemotherapy according to the institutional guidelines, prior to screening.
10. If indicated, patient has completed adjuvant radiotherapy according to the institutional guidelines, prior to screening.
11. Patient has no contraindication for the adjuvant ET in the trial and is planned to be treated with ET for 5 years (since randomization date) or more.
12. Patient may have already received any standard neoadjuvant and/or adjuvant ET at the time of PICF signature, but randomization should occur within 12 months of the initial start date of ET. Ovarian suppression or short term ET for fertility preservation is not considered neoadjuvant/adjuvant ET. If patient was receiving tamoxifen or toremifene as adjuvant ET, a washout period of 5 half-lives (i.e. 35 days) prior to randomization is required (during that period patient can take AI).
13. Patient has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
14. Patient has adequate bone marrow and organ function as defined by the following local laboratory values: • Absolute neutrophil count (ANC) ≥ 1.5 × 109/L • Platelets ≥ 100 × 109/L • Hemoglobin ≥ 9.0 g/dL • Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m2 according to the Modification of Diet in Renal Disease (MDRD) formula • Alanine transaminase (ALT) < 2.5 × Upper Limit Normal (ULN) • Aspartate transaminase (AST) < 2.5 × ULN • Total serum bilirubin < ULN; or total bilirubin ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN in patients with well documented Gilbert’s Syndrome • International normalized ratio (INR) ≤ 1.5 (unless the patient is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within 7 days prior to randomization) • Patient must have the following laboratory values within normal limits or corrected to within normal limits with supplements (the local laboratory value should be documented within normal limits after the correction) before randomization: • Potassium • Magnesium • Total Calcium (corrected for serum albumin)
15. Standard 12-lead ECG values assessed by a central laboratory, as: • QTcF interval (QT interval using Fridericia’s correction) at screening < 450 milliseconds (msec) • Resting heart rate 50-90 beats per minute (determined from the ECG)
16. Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures.
17. Women of childbearing potential (CBP), defined as all women physiologically capable of becoming pregnant (see Inclusion Criterion #18 for additional information), must have confirmed negative serum pregnancy test (for β-hCG) within 14 days prior to randomization
18. Women of CBP must be willing to use highly effective methods of contraception. Contraception must continue during the trial treatment and for 21 days after stopping the treatment. Highly effective contraception methods include: • Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking trial treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. • Male partner sterilization (at least 6 months prior to randomization). For female patients on the trial the vasectomized male partner should be the sole partner for that patient. If vasectomy of the male partner is the highly effective method of contraception chosen, the success of the vasectomy should be medically confirmed according to local practice. • Placement of an intrauterine device (IUD).

Exclusion criteria 18

1. Patient has received any CDK4/6 inhibitor
2. Patient has known history of human immunodeficiency virus (HIV) infection (testing is not mandatory, unless required by local regulation).
3. Patient has known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (testing is not mandatory, unless required by local regulation).
4. Patient has received prior treatment with tamoxifen, raloxifene or AIs for reduction in risk (“chemoprevention”) of breast cancer and/or treatment for osteoporosis within the last 2 years prior to randomization. Patient is concurrently using hormone replacement therapy
5. Patient has received prior treatment with anthracyclines at cumulative doses of 450 mg/m² or more for doxorubicin, or 900 mg/m² or more for epirubicin
6. Patient with a known hypersensitivity to any of the excipients of ribociclib and/or ET (e.g. rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption, and soy allergy).
7. Patient with distant metastases of breast cancer beyond regional lymph nodes (stage IV according to AJCC 8th edition) and/or evidence of recurrence after curative surgery
8. Patient is concurrently using other anti-neoplastic therapy with the exception of adjuvant ET (see Inclusion Criterion #12).
9. Patient has had major surgery, chemotherapy or radiotherapy within 14 days prior to randomization.
10. Patient has not recovered from clinical and laboratory acute toxicities related to prior anti-cancer therapies to a NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03 Grade ≤1 at day of randomization. Exceptions to this criterion: patients with any grade of alopecia, amenorrhea, grade 2 neuropathy are allowed to enter the trial or other toxicities not considered a safety risk for the patient as per Investigator’s discretion, are allowed to enter the tria l
11. Patient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 2 years before randomization.
12. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:  History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft within 6 months prior to trial entry.  Documented cardiomyopathy.  Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) (testing not mandatory)  Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: • Risk factors for Torsades de Pointes (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia. • Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication (e.g. within 5 half-lives or 7 days prior to starting trial treatment). • Inability to determine the QTcF interval.  Clinically significant cardiac arrhythmias (e.g. ventricular  tachycardia), complete left bundle branch block, high-grade  Atrioventricular (AV) block (e.g. bifascicular block, Mobitz type II  and third degree AV block).  Uncontrolled arterial hypertension with systolic blood pressure >  160 mmHg.
13. Patient is currently receiving any of the following substances within 7 days before randomization: • Concomitant medications, herbal supplements, and/or fruits (e.g. grapefruit, pummellos, starfruit, Seville oranges) and their juices that are known as strong inhibitors or inducers of CYP3A4/5 • Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
14. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting trial treatment, or has not fully recovered from side effects of such treatment.
15. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the oral trial treatments (e.g. uncontrolled ulcerative diseases, uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, or small bowel resection).
16. 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 trial or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, liver cirrhosis or any other significant liver disease, active untreated or uncontrolled fungal, bacterial or viral infections, active infection requiring systemic antibacterial therapy, etc.) or limit life expectancy to ≤5 years.
17. Participation in other studies involving investigational drug(s) within 30 days prior to randomization or within 5 half-lives of the investigational drug(s) (whichever is longer), or participation in any other type of medical research judged not to be scientifically or medically compatible with this trial. If the patient is enrolled or planned to be enrolled in another study that does not involve an investigational drug, the agreement of the Medical Monitor is required to establish eligibility.
18. Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the trial.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. iDFS using STEEP criteria, as assessed by Investigator

Secondary endpoints 6

1. RFS using STEEP criteria
2. DDFS using STEEP criteria
3. OS defined as time from date of randomization to date of death due to any cause
4. Change from baseline in the physical functioning sub-scale score and global health status/ QoL scale score as assessed by EORTC QLQ-C30
5. Frequency and severity of AEs, laboratory and Electrocardiogram (ECG) abnormalities
6. PK parameters such as Ctrough and other applicable parameters for ribociclib

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 11

Locations

10 EU/EEA countries · 172 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 206 files

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

Application history

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