A PoC Study to Evaluate Treatments' Efficacy by Monitoring MRD Using ctDNA in HR-positive/HER2-negative EBC Population

Inclusion Criteria41

• Eligibility criteria for the surveillance phase:
• Signed informed consent form (ICF) prior to participation in any Studyrelated activities.
• Male or female patients aged 18 years or older.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Histologically proven primary HR-positive according to the updated American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) 2020 guidelines and HER2-negative BC as per ASCO/CAP 2018 criteria based on local testing on the most recent analyzed biopsy.
• Patients with high-risk early-stage BC according to at least one of the following criteria: a. If there is no previous neoadjuvant chemotherapy: i. pN2-N3 or ii. pN1 (including micrometastasis - pN1mi) if:
• \. pT3-T4, or 2. pT2 and high genomic risk and/or histological grade III and/or Ki 67≥30%. b. If patients have received previous neoadjuvant chemotherapy, they must have had residual invasive disease defined as at least one of the following: i. Residual invasive disease in lymph nodes (ypN+, including ypN1mi) ii. ypN0 with residual invasive disease in breast if:
• cT3-4, or
• cT2 and high genomic risk and / or histological grade III and / or Ki67≥30%. Note: Genomic risk using platforms such as Oncotype Dx, Prosigna or Mammaprint won't be assessed for the screening to participate in the Study. However, patients with the detailed scores assessed prior to Study inclusion, may be eligible.
• \. On adjuvant treatment with ET for at least two years and no more than seven years at the time of Study enrolment with an additional three years of ET planned, and at least 6 months prior to enrolment on the same ET treatment with AI or tamoxifen (LHRH is mandatory for men and premenopausal women receiving AI, as well as for premenopausal women treated with tamoxifen, except in cases of bilateral oophorectomy.) Note: Pre-menopausal patients treated with tamoxifen alone are excluded.
• \. Prior treatment with cyclin-dependent kinases 4/6 (CDK4/6) inhibitors will be allowed in the case of an interval of at least 12 months between the last dose and inclusion in the trial.
• \. No prior treatment with SERDs will be allowed.
• \. Willingness and ability to provide tissue from one archival tumor tissue sample (either from diagnostic biopsy, primary surgery, or where available from a residual disease post-neoadjuvant therapy).
• Note: Patients with multifocal BC may be enrolled, if archival tissue samples from at least two tumors are available and after histopathological examination, all tumors meet pathologic criteria for HR-positive and HER2-negative BC.
• \. Absence of metastatic disease by routine clinical assessment (computed tomography \[CT\] scan of the thorax and abdomen, and bone scan or positron emission tomography \[PET\] scan). confirmed no longer than three months prior to Study inclusion.
• \. Patients must have had surgery for their primary BC with documented clear margins (as per local guidelines) and they must have received radiotherapy if indicated (as per local guidelines).
• \. Patients must be able and willing to adhere to Study procedures.
• Signed treatment ICF prior to Study inclusion.
• Male or female patients aged 18 years or older.
• ctDNA positivity with no evidence of clinical or radiologic recurrence by standard assessments (e.g.: breast ultrasound, staging scans, RMN).
• ECOG performance status 0 or 1.
• Patients must have received the same ET during at least the last 6 months. A temporary discontinuation of \< 90 days during the surveillance phase is allowed.
• Receiving LHRH agonist therapy alongside the same ET treatment for at least 90 days prior to initiation of one of the available Study treatments if male or pre-menopausal.
• Prior treatment with cyclin-dependent kinases 4/6 (CDK4/6) inhibitors will be allowed in the case of an interval of at least 12 months between the last dose and inclusion in the trial.
• No prior treatment with SERDs will be allowed.
• Absence of metastatic disease by routine clinical assessment (computed tomography \[CT\] scan of the thorax and abdomen, and bone scan or positron emission tomography \[PET\] scan). confirmed no longer than three months prior to Study inclusion.
• Patients must have had surgery for their primary BC with documented clear margins (as per local guidelines) ) and they must have received radiotherapy if indicated (as per local guidelines).
• Willingness and ability to provide tissue from one archival tumor tissue sample (either from diagnostic biopsy, primary surgery, or where available from a residual disease post-neoadjuvant therapy).
• Female of reproductive potential and male patients with female partners of childbearing potential, must remain abstinent and truly abstain from sexual activity (refrains from heterosexual intercourse) or use locallyrecognized adequate methods of contraception (described as that with a failure rate \<1%) for the duration of trial treatment. In addition, patients must follow these guidelines for a certain period of time after the last dose of trial treatment, specified in the protocol depending on which treatment arm the patient is allocated in. During this indicated period of time, female and male patients must as well refrain from donating eggs or sperm.
• Note: Female patients will be deemed not of childbearing potential if they are post-menopausal or have had irreversible sterilization. Well-defined pre-menopausal status refers to women who have not reached the postmenopausal state because they are not permanently infertile due to prior bilateral oophorectomy, age ≥60 years or age \<60 years with amenorrhea for ≥12 months and estradiol and follicle-stimulating hormone (FSH) levels in the post-menopausal range.
• Resolution of all acute toxic effects of prior anti-cancer therapy to Grade ≤1 as determined by the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v) 5.0 (except for alopecia, or other toxicities not considered a safety risk for the patient at investigator's discretion). Adverse events (AEs) of current ET treatment are not included.
• Adequate hematologic and organ function within 14 days before the first Study treatment on Day 1 of Cycle 1, defined by the following:
• Hematological (without platelet, red blood cell (RBC) transfusion, and/or granulocyte colony-stimulating factor support within 7 days before first Study treatment dose): White blood cell (WBC) count \> 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 9.0 g/dL (≥ 5.6 mmol/L).
• Hepatic: Serum albumin ≥ 3 g/dL; Bilirubin ≤ 1.5 times the upper limit of normal (ULN) (≤ 3 x ULN in the case of Gilbert's disease); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN; alkaline phosphatase (ALP) ≤ 2 × ULN.
• Renal: serum creatinine level ≤ 1.5 × the upper limit of normal (ULN) or an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m², as calculated using the 2021 CKD-EPI creatinine equation (National Kidney Foundation, 2021).
• Note: eGFR should be determined using the following standardized CKDEPI 2021 formula (without race adjustment): eGFR (mL/min/1.73 m²) = 142 × min(Scr/κ, 1)\^α × max(Scr/κ, 1)\^-1.200 × 0.9938\^Age × 1.012 \[if female\]. Scr = serum creatinine in mg/dL, κ = 0.7 for females; 0.9 for male; α = - 0.241 for females; -0.302 for males; min(Scr/κ, 1) = the lesser of Scr/κ or 1; max(Scr/κ, 1) = the greater of Scr/κ or 1; Age = age in years; The multiplication factor 1.012 is applied only for females.
• Participants who are able and willing to swallow, retain, and absorb oral medication.
• Patients must be able and willing to adhere to Study procedures.
• \. Patients with prior diagnosis of thrombosis might be included as long as they are under stable anti-coagulation regimen therapy 28 days prior to starting treatment with abemaciclib.
• Confirmation of biomarker eligibility (detection of specified mutation(s) of PIK3CA via specified test: Qiagen therascreen PIK3CA RGQ PCR PCR kit - CE-IVD). This determination will be done in tumor tissue.
• No prior treatment with any phosphatidylinositol 3-kinase (PI3K), Akt, or mammalian target of rapamycin (mTOR) inhibitors, or any agent whose mechanism of action is to inhibit the PI3K/Akt/mTOR pathway.