Advanced hormone receptor-positive/HER2-negative/HER2-Enriched breast cancer

Prior treatment

• Patients meeting any of the following criteria are not eligible for inclusion in this study: Prior therapy with any CDK4/6 inhibitors in the metastatic setting. Note: Patients who received (neo) adjuvant iCDK 4/6 therapy for breast cancer are eligible. The disease-free interval since the last (neo)adjuvant iCDK 4/6 dose must be equal or greater than 12 months prior to randomization.
• 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 anti-bacterial therapy, etc.) or limit life expectancy to ≤6 months.
• 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.
• Patient is currently receiving or has received systemic corticosteroids (>10 mg daily of prednisone or equivalent) ≤ 2 weeks prior to starting trial treatment, or has not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: a short duration (<5 days) of systemic corticosteroids; any duration of topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airways diseases), eye drops or local injections (e.g. intra-articular).
• Patient is currently receiving any of the following substances within 7 days before randomization: o Concomitant medications, herbal supplements, and/or fruits (e.g. grapefruit, pomelos, starfruit, Seville oranges) and their juices that are known as strong inhibitors or inducers of CYP3A4/5. o Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
• Patient has received prior treatment with chemotherapy for advanced / metastatic breast cancer. Note: neoadjuvant/ adjuvant chemotherapy for early breast cancer is allowed.
• Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways
• Infection (including tuberculosis infection, etc.) requiring systemic antibacterial, antifungal or antiviral therapy within 14 days prior to first dose of study drugs.
• Prior allogeneic stem cell transplantation or organ transplantation
• Was administered a live vaccine ≤ 28 days before first dose of study drug Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.
• Patient has received extended-field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior to enrollment and has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia or other toxicities not considered a safety risk for the patient at investigator’s discretion). Patients in whom ≥ 25% of the bone marrow has been previously irradiated are also excluded[89].
• Has unresolved toxicities from previous anticancer therapy or major surgical procedures not yet resolved to NCI CTCAE version 4.03 Grade ≤ 1 or baseline at the day of inclusion. Exceptions to this criterion: patients with any grade of alopecia, amenorrhea, grade 2 neuropathy, or other toxicities not considered a safety risk for the patient as per Investigator’s discretion, are allowed to enter the trial. Note: Placement of central venous access catheter(s) (e.g., port or similar) is not considered a major surgical procedure and is therefore permitted.
• Known active central nervous system metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate if radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging Note: imaging repetition should be performed during study screening, clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.

Other illness

• Patient has impairment of 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).
• For Basal-like cohort only: History of hypersensitivity reactions to paclitaxel or other drugs formulated in the same solvent as paclitaxel (polyoxyethylated castor oil).
• A history of severe hypersensitivity reactions to other monoclonal antibodies
• Active autoimmune diseases or history of autoimmune diseases that may relapse. (refer to Appendix 3 for a list of conditions) Note: Patients with the following diseases are not excluded and may proceed to further screening: a. Controlled Type I diabetes b. Hypothyroidism (provided it is managed with hormone replacement therapy only) c. Controlled celiac disease d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) e. Any other disease that is not expected to recur in the absence of external triggering factors
• History of interstitial lung disease, non-infectious pneumonitis or uncontrolled lung diseases including pulmonary fibrosis, acute lung diseases, etc. Patients with significantly impaired pulmonary function, or who require supplemental oxygen at baseline must undergo an assessment of pulmonary function at screening
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ), or other malignant tumors with an expected curative outcome after medical monitor approval that have undergone potentially curative therapy are not excluded.
• Known history of Human Immunodeficiency Virus (HIV). Note: Testing for HIV must be performed at sites if required by local practice.
• Patient has known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection Note: testing is not mandatory, unless required by local regulation.

Lab values

• Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following: o History of documented myocardial infarction, angina pectoris, symptomatic pericarditis, or coronary artery bypass graft within 6 months prior to trial entry. o Documented cardiomyopathy. o Pulmonary embolism ≤ 28 days before first dose of study drug o Any history of cerebrovascular accident ≤ 6 months before first dose of study drug o Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) (testing not mandatory). o Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: o Risk factors for Torsades de Pointes (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia. o 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). o Inability to determine the QTcF interval. o 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). o Uncontrolled arterial hypertension with systolic blood pressure > 180 mmHg or hypotension <90 mmHg.
• For HER2-E cohort only: Patient with a known hypersensitivity to any of the excipients of ribociclib, palbociclib and/or endocrine therapy (e.g. rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption, and soy allergy).

Other

• Pregnant or breast-feeding women or women who plan to become pregnant or breast-feed during the trial.
• Not able to understand and to comply with study instructions and requirements according to investigator criteria.
• Uncontrolled pleural effusion, pericardial effusion, or ascites (Note: patients with indwelling catheters, such as PleurX® are allowed).

• Signed informed consent must be obtained prior to any trial-specific screening procedure. Signed informed molecular pre-screening consent must be obtained prior to PAM50 test.
• Adequate hematologic and end-organ function, defined by the following laboratory results (Table 2): Table 2. Adequate organ function laboratory values System Laboratory Value Hematological Absolute neutrophil count (ANC) ≥1500/µL Platelets ≥100 000/µL Hemoglobin ≥10.0 g/dL or ≥6.21 mmol/L Renal Creatinine OR Measured or calculateda creatinine clearance (MDRD GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for patient with creatinine levels >1.5 × institutional ULN Potassium, , calcium corrected for serum albumin and magnesium within normal limits or corrected to within normal limits with supplements before first dose of the study medication. Hepatic Total bilirubin 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 AST (SGOT) and ALT (SGPT) ≤3 × ULN (≤5 × ULN for patients with liver metastases) Coagulation International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT or a PTT is within therapeutic range of intended use of anticoagulants ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal. a Creatinine clearance (CrCl) should be calculated per institutional standard
• 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 #13 for additional information), must have confirmed negative serum pregnancy test within 7 days prior to randomization.
• Women of CBP must be willing to use highly effective methods of contraception. Contraception must continue during the trial treatment after stopping the treatment according to protocol. The duration depends on the treatment received. Highly effective contraception methods include: o 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. o 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. o 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. o Placement of an intrauterine device (IUD). Notes: Use of oral (estrogen and progesterone), transdermal, injected, implanted, hormone containing intrauterine system, or any other hormonal methods of contraception is not allowed in this trial. Women are considered of CBP unless: they have had ≥ 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks prior to randomization. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment she is considered not of CBP. After the end of trial treatment, patients should use effective contraception according to local guidelines.
• Postmenopausal, as defined by at least one of the following criteria: o Prior bilateral oophorectomy, o Age ≥60, o Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range. o If taking tamoxifen or toremifene and age <60, then FSH and plasma estradiol level in postmenopausal range. OR Pre/perimenopausal, i.e., not meeting the criteria for being postmenopausal: o Pre/perimenopausal women can be enrolled to receive treatment with endocrine therapy + iCDK4/6 if amenable to be treated with the LHRH agonist (e.g. triptoreline, leuprolide, gosereline) approved for use in metastatic breast cancer in the respective countries. LHRH agonist is recommended to be administered before day 1 at Cycle 1 and every 28 days. Note: For women with therapy-induced amenorrhea, serial measurements of FSH and/or estradiol are needed to ensure postmenopausal status.
• Patients must have the ability to swallow oral medication.
• Patient must have a 6-lead or 12-lead ECG with ALL of the following parameters at screening: a) QTcF interval (QT interval using Fridericia’s correction) at screening < 450 msec. b) Resting heart rate 50-100 beats per minute (determined from the ECG).
• For Basal-like cohort only: Non-sterile males must be willing to use a highly effective method of birth control for the duration of the study and for ≥ 120 days after the last dose of tislelizumab. o A sterile male is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility. o Males with known “low sperm counts” (consistent with “sub-fertility”) are not to be considered sterile for purposes of this study.
• Male/female patients who are at least 18 years of age on the day of signing informed consent.
• Histologically documented HR-positive and HER2-negative breast cancer by local testing: a) HER2 negativity is defined as either of the following: Immunohistochemistry (IHC) 0, IHC 1+ or IHC2+/in situ hybridization (ISH) negative as per most recent American Society of Clinical Oncology (ASCO)-College of American Pathologists Guideline (CAP) guideline according to the local laboratory as determined on the most recently analyzed tissue sample. b) ER and/or PgR positivity are defined as >1% of cells expressing HR via IHC analysis as per most recent ASCO-CAP guideline according to the local laboratory as determined on the most recently analyzed tissue sample. c) ER-positive by IHC according to the following criteria (local assessment): ER-positive ≤ 95% or Allred score < 8.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Prior radiation therapy for metastatic disease is permitted. Patients must have recovered from radiotherapy toxicities prior to inclusion.
• Patient has advanced (loco regionally recurrent not amenable to curative therapy or metastatic) breast cancer. Patients may be: o newly diagnosed advanced breast cancer, treatment naïve o relapsed with documented evidence of progression more than 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease. o relapsed with documented evidence of progression on or within 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease. o relapsed with documented evidence of progression more than 12 months from completion of adjuvant endocrine therapy and then subsequently progressed with documented evidence of progression after one line of endocrine therapy (with either an antiestrogen or an aromatase inhibitor) for metastatic disease. o newly diagnosed advanced breast cancer, then progressed with documented evidence of progression after one line of endocrine therapy (with either an antiestrogen or an aromatase inhibitor) Note: In all cases, patients may start letrozole or fulvestrant ≤ 28 days for advanced disease prior to inclusion in this trial, this is not considered a prior line of therapy. Note: Patient who relapsed with documented evidence of relapse on/or within 12 months from completion of adjuvant endocrine therapy and then subsequently progressed with documented evidence of progression after one line of endocrine therapy (with either an antiestrogen or an aromatase inhibitor) for metastatic disease will NOT be included in the study.
• Availability of FFPE tumor block for biomarker analysis, obtained during metastatic period. The tumor tissue should be of good quality based on total and viable tumor content and must be evaluated centrally for PAM50 analysis prior to enrollment. Patients whose tumor tissue is not evaluable for central testing are not eligible. Note: Acceptable samples include core needle biopsies for deep tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions or biopsies from bone metastases. Fine needle aspiration, brushing, cell pellet from pleural effusion and lavage samples are not acceptable. Note: Untreated primary tumors from patients that progress within the first 24 months of endocrine (neo)adjuvant treatment start are acceptable for PAM50 analysis, if those tumors result in a luminal subtype further subtype analysis can be perform on sample obtained after metastatic recurrence.
• HER2-E or Basal-like subtype as per central PAM50 analysis.
• Measurable disease or non-measurable disease (but evaluable), as defined by RECIST v1.1. (Note: Previously irradiated lesions can be considered as measurable disease only if disease progression has been unequivocally documented at that site since radiation. Non measurable lesions are all non-measured lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), bone, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified and evaluated by physical exam that is not measurable by reproducible imaging techniques.