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

Phase 1

Recruiting

• Conditions: hormone receptor (HR)-positive, HER2-negative,early breast cancer (EBC).; MedDRA version: 20.0Level: LLTClassification code: 10006203Term: Breast cancer stage unspecified Class: 10029104; MedDRA version: 23.0Level: LLTClassification code: 10070575Term: Estrogen receptor positive breast cancer Class: 10029104; Therapeutic area: Diseases [C] - Neoplasms [C04]

• Registration Number: CTIS2023-510357-42-00
• Lead Sponsor: ovartis Pharma AG

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2024-06-10
• Last Update Posted: 21 August 2024

Recruitment & Eligibility

• Status: Recruiting
• Sex: All
• Target Recruitment: 4992

Inclusion Criteria

Signed and dated Patient Informed Consent Form (PICF) obtained prior to any trial-specific screening procedure., If indicated, patient has completed adjuvant radiotherapy according to the institutional guidelines, prior to screening., 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., 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)., Patient has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1., 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), 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), Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures., 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 ß-hCG) within 14 days prior to randomization, 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. •

Exclusion Criteria

Patient has received any CDK4/6 inhibitor, 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, Patient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 2 years before randomization., 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., 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, 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., 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)., 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., Partici

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To compare iDFS for ribociclib + ET versus ET in patients with HR-positive,<br>HER2-negative, EBC;Secondary Objective: To evaluate the two treatment arms with respect to recurrence-free survival (RFS), To evaluate the two treatment arms with respect to distant disease free survival (DDFS), To evaluate the two treatment arms with respect to overall survival (OS), To evaluate patient reported outcomes (PRO) for health-related quality of life (QoL) in the two treatment arms, To evaluate safety and tolerability of the treatment regimen, To characterize the pharmacokinetics (PK) of ribociclib when given in combination with NSAI (and goserelin if applicable);Primary end point(s): iDFS using STEEP criteria, as assessed by Investigator

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s):RFS using STEEP criteria;Secondary end point(s):DDFS using STEEP criteria;Secondary end point(s):OS defined as time from date of randomization to date of death due to any cause;Secondary end point(s):Change from baseline in the physical functioning sub-scale score and global health status/ QoL scale score as assessed by EORTC QLQ-C30;Secondary end point(s):Frequency and severity of AEs, laboratory and Electrocardiogram (ECG) abnormalities;Secondary end point(s):PK parameters such as Ctrough and other applicable parameters for ribociclib