Liquid-biopsy Informed Platform Trial to Evaluate CDK4/6-inhibitor Resistant ER+/HER2- Metastatic Breast Cancer

Inclusion Criteria:

• Patients must have histologically and/or cytologically confirmed, advanced /metastatic breast cancer, ER >10% and not HER2 overexpressing/amplified as perASCO/CAP criteria. Patients with locally advanced or inflammatory disease withoutdistant metastases that is potentially resectable or treatable with curative intentare not eligible

• All patients must have a formalin fixed paraffin embedded tissue block (from primaryor metastatic tumour) available and must have provided informed consent for therelease of the block

• Patients must have had objective disease progression demonstrated on (defined aswhile taking or within 8 weeks of the last dose) first line CDK4/6i + ET for MBC.Patients who discontinued CDK4/6i + ET without disease progression more than 8 weeksprior to objective disease progression (toxicity, patient request) are not eligible.Patients must have received at least 24 weeks of first line CDK4/6i + ET therapy

• Presence of clinically and/or radiologically documented disease. All radiologystudies must be performed within 21 days prior to enrollment (within 28 days ifnegative). All patients must have measurable disease as defined by RECIST 1.1.

• The criteria for defining measurable disease are as follows:

• Chest x-ray ≥ 20 mm

• CT scan (with slice thickness of 5 mm) ≥ 10 mm: longest diameter

• Physical exam (using calipers) ≥ 10 mm

• Lymph nodes by CT scan ≥ 15 mm: measured in short axis

• Patients must be ≥ 18 years of age

• Patients must have an ECOG performance status 0 or 1

• Patients must have a life expectancy ≥ 3 months.

• Hemoglobin ≥90 g/L*

• Absolute neutrophils ≥ 1.5 x 10^9/L (1500/µL)

• Platelets ≥ 100 x 109/L (100 x 10^3/µL)

• Bilirubin ≤ 1.5 x ULN (upper limit of normal)**

• AST & ALT ≤ 2.5 x ULN

• ≤ 5.0 x ULN if patient has liver metastases

• Serum creatinine ≤ 1.5 x ULN, Creatinine clearance ≥50 mL/min

• All patients must have received at least 24 weeks of prior CDK4/6i in combinationwith first line ET for advanced or metastatic disease and have had diseaseprogression on or within 8 weeks of the last dose of CDK4/6i. Patients who haveprogressed on, or within 12 months of completion of adjuvant therapy with anaromatase inhibitor may be treated with fulvestrant instead of an aromataseinhibitor combined with CDK4/6 inhibitor.

In addition, the following systemic therapies may have been given after CDK4/6i / ET prior to screening / enrollment to this study:

• For enrollment to "second line" substudies:

• An additional single agent non-fulvestrant/SERD endocrine therapy in thepalliative setting is permitted provided patient remains eligible for and canaccess fulvestrant treatment. Patients who have received prior fulvestrant/SERDare not eligible for fulvestrant containing substudies. Contact CCTG in case ofany other prior endocrine therapy other than an aromatase inhibitor ortamoxifen.

• For enrollment to "third line" substudies:

• Non-SERD endocrine therapy and targeted agents alone or in combination.

• Patients who have received a prior targeted agent may not be eligible forsubstudies that contain the same class of agent. Contact CCTG.

• Note: if a patient has not had fulvrestrant/SERD prior to enrollment to "3rdline: substudy, single agent fulvestrant/SERD must be given prior to enrollment (unless not possible for reasons such as fulvestrant/SERD not standard of care / not funded in province, patient cannot receive intramuscular injection;contact CCTG for other scenarios).

• Patients may also have received adjuvant/neoadjuvant systemic therapies; howevercytotoxic chemotherapy or antibody drug conjugates (ADC) in the palliative settingare not permissible.

• Patients receiving LHRH agonists (for example premenopausal patients) may continue,but may not start LHRH agonist within 12 weeks of enrollment.

• Consult CCTG for other scenarios (for example where short course of other ET isgiven prior to CDKi + ET, patients who have received investigational drugs, vaccinesor immunotherapies) as certain patients may be eligible.

• All reversible prior toxicity related to prior therapies must have recovered tograde ≤ 1 (consult CCTG in the case of irreversible toxicity) and have adequatewashout as follows (screening may occur during the washout period): Longest of thefollowing (for questions or any proposed variance, please discuss with CCTG prior topatient enrollment): Two weeks; 5 half-lives for investigational agents; standardcycle length of standard therapies

• Patients must not have received a transfusion (platelets or red blood cells) orcolony stimulating factors ≤ 4 weeks prior to initiating treatment substudy therapy.

• Surgery: Prior surgery is permitted provided that a minimum of at least 28 days haveelapsed between any major surgical procedure and date of enrollment, and that woundhealing has occurred.

• Radiation: Prior external beam radiation is permitted provided a minimum of 28 days (4 weeks) have elapsed between the last dose of radiation and date of enrollment.Exceptions may be made for low-dose, non-myelosuppressive radiotherapy afterconsultation with CCTG. Concurrent radiotherapy is not permitted.

• Patients must be registered and provide consent prior to blood collection forscreening. The screening blood sample cannot be sent for analysis prior to screeningregistration.

• Patient consent must be appropriately obtained in accordance with applicable localand regulatory requirements. Each patient must sign a consent form prior to bothscreening registration as well as enrollment to a specific substudy to documenttheir willingness to participate.

• Patients must be accessible for treatment and follow up. Patients enrolled on thistrial must be treated and followed at the participating centre

• In accordance with CCTG policy, substudy treatment is to begin within 2 working daysof patient enrollment.

• Women/men of childbearing potential must have agreed to use a highly effectivecontraceptive method.

Exclusion Criteria:

• Patients with a history of other malignancies, including Myelodysplastic syndrome (MDS) or Acute myeloid leukemia (AML) except: adequately treated non-melanoma skincancer, curatively treated in-situ cancer of the cervix, or other malignanciescuratively treated with no evidence of disease for ˃ 2 years and which do notrequire ongoing treatment.

• Patients with active or uncontrolled infections or with serious illnesses or medicalconditions which would not permit the patient to be managed according to protocol.

• Infection includes but is not limited to active infection requiring systemictherapy and active or known human immunodeficiency virus (HIV) with detectableviral load, known hepatitis B surface antigen or positive hepatitis C antibody

• Pneumonitis or any history of pneumonitis requiring steroids (any dose)

• Participant has received a live vaccine within 30 days of planned start ofstudy therapy. COVID19 vaccines that do not contain live viruses are allowed.

• Known primary immunodeficiency

• Patients with recent clinically significant cardiac disease, including:

• angina pectoris, symptomatic pericarditis, coronary artery bypass grafting,coronary angioplasty, or stenting, or myocardial infarction in the previous 12months;

• history of documented congestive heart failure (New York Heart Associationfunctional classification III-IV) or cardiomyopathy

• uncontrolled hypertension (per Canadian guidelines)

• All patients should have a LVEF ≥ 50%.

• Patients with HER2 positive breast cancer (based on the most recent assessment,according to ASCO/CAP criteria).

• History of hypersensitivity to any of the study drugs or their components.

• Patients may not receive concurrent treatment with other anti-cancer therapy (otherthan bone-targeted therapy, if already taking and stable) or investigational agentswhile on protocol therapy.

• Patients with prior allogenic bone marrow transplant or double umbilical cord bloodtransplantation (dUCBT).

• Pregnant or breastfeeding women.

• Patients with history of central nervous system metastases or spinal cordcompression unless they have received definitive treatment such as resection orradiation, are clinically stable and do not require corticosteroids; corticosteroidsmust have been discontinued at least 7 days prior to enrollment.

• Patients who are unable to swallow oral medication and/or have impairment ofgastrointestinal (GI) function or GI disease that may significantly alter theabsorption of the study drugs (e.g. Crohn's disease, ulcerative diseases,uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, active bowelinflammation (e.g. diverticulitis) or small bowel resection), unless agreed withCCTG (exceptions may be given if a parenteral treatment substudy isavailable/appropriate).

• Patients with a history of non-compliance to medical regimens.

• See Section 7.3 and individual treatment substudies for a list of concomitantmedications that are not permitted.

• Many substudies include drugs that have a risk for thrombocytopenia; therefore,participants should be advised to use caution when taking oral anticoagulants (e.g.warfarin) and antiplatelet drugs (e.g. aspirin).