Clinical Trial Finder

Inclusion Criteria:

1. Participants must have histologically confirmed hormone receptor positive (HR+) HER2 negative metastatic breast cancer. Cut-off values for positive/negative staining should be as per standard practice in accordance with ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines. 2. Participants must be candidates for initiation of CDK4/6 inhibitor therapy, either palbociclib or ribociclib, in combination with endocrine therapy in the first line setting, in the judgement of the treating provider. The planned endocrine partner can be an aromatase inhibitor (letrozole, anastrozole, exemestane) or fulvestrant, selected through patient/provider choice. 3. People aged 65 years or older. 4. Adequate bone marrow and organ function.

• - Absolute neutrophil count > 1,000/µL.

• - Platelets > 100,000/µL.

• - Hemoglobin> 9g/dL.

• - Total bilirubin <5 x institutional upper limit of normal (ULN) (participants with documented Gilbert's disease are allowed total bilirubin up to 1.5X ULN) - AST (SGOT)/ALT (SGPT) <5 x institutional ULN, or ≤ 5 x ULN for subjects with documented metastatic disease to the liver.

• - Creatinine < institutional ULN or creatinine clearance > 30 mL/min/1.73 m2 for subjects with creatinine levels above institutional ULN.

• - Baseline QTc < 480 ms (only for ribociclib patients) 5.

Ability to understand and the willingness to sign a written informed consent document. 6. Participants with known HIV infection without active opportunistic infections are eligible.

Exclusion Criteria:

1. Previous treatment with a CDK4/6 inhibitor for metastatic breast cancer, or previous treatment within the past 12 months with a CDK4/6 inhibitor in the neo/adjuvant breast cancer setting. 2. No prior chemotherapy for metastatic breast cancer. 3. Participants who may have had more than 30 days of endocrine therapy as monotherapy in the first-line metastatic setting prior to entering the study. 4. Known history of intolerance or allergy to the planned agents used in this trial. 5. Uncontrolled intercurrent illness that, as evaluated by the treating clinician, would hinder compliance with study requirements. 6. Participants who are receiving concurrent therapy with other investigational agents. 7. Patients with stable and/or treated brain metastases are allowed. Patients with rapidly progressive brain metastases are excluded. 8. Patients with active or chronic Hepatitis B or C are eligible provided they meet liver function laboratory criteria and are not on medication with a known interaction with the study agents. 9. Current use of drugs listed in Appendix 14 that are known to prolong the QT interval.

The CDK4/6 Inhibitor Dosing Knowledge Study (CDK Study) will study CDK4/6 inhibitor dosing regimens in patients 65 or older with MBC. The overarching goal of this pragmatic, randomized trial is to compare an "indicated" dosing approach, as listed on the FDA-approved drug label, that starts at the full dose of a CDK4/6 inhibitor (palbociclib or ribociclib) with dose reduction based on tolerability versus a "titrated" dosing approach that starts at a lower dose of a CDK4/6 inhibitor and then titrates up to full dose as tolerated. CDK4/6 inhibitors will be given in combination with endocrine therapy (either an aromatase inhibitor (AI) or fulvestrant) based on the choice of the treating clinician. The primary endpoint will be time to treatment discontinuation (TTD), defined as the time from randomization to last dose of the CDK4/6 inhibitor. The hypothesis is that starting low and escalating as tolerated will help older patients (> 65 years) stay on therapy longer. Eligibility criteria are broad to allow patients who are not typically included in clinical trials to participate, allowing for a more representative sample of participants. The investigators will conduct sub-group analyses based on age (65-74 years vs.#46; ≥75 years) and baseline frailty scores. This study builds upon the lessons learned from prior studies with CDK4/6 inhibitors. The investigators will augment the standard assessment of treatment toxicities assessed by the health care team with prospectively collected patient-reported outcomes data to better reflect how participants tolerate the different dosing approaches.

Arms

Experimental: Arm 1: Indicated Dose

Arm 1 of the study is the indicated dosing regimen, provided in the FDA approved drug label: participants will start cycle 1 with either 125mg dose of palbociclib or 600mg dose of ribociclib, in combination with endocrine therapy (AI or fulvestrant).

Experimental: Arm 2: Titrated Dose

Arm 2 is the titrated dosing regimen: participants will start cycle 1 with either 100 mg or 75 mg dose of palbociclib or 400 mg or 200 mg dose of ribociclib, in combination with endocrine therapy (AI or fulvestrant). For cycle 2 and for subsequent cycles, escalation to the indicated dose will be based on treatment tolerance.

Interventions

Drug: - Palbociclib

Approved dosing for palbociclib (125 mg orally daily on days 1-21 of 28-day cycle) vs. TTD using titrated dosing approach with the same schedule but starting at a lower dose of palbociclib (100 mg or 75 mg) and escalating the dose if well-tolerated in combination with provider/patient choice of endocrine therapy.

Drug: - Ribociclib

Approved dosing of ribociclib (600 mg orally daily on days 1-21 of 28-day cycle) vs. TTD using titrated dosing approach with the same schedule but starting at a lower dose of ribociclib (400 mg or 200 mg) and escalating the dose if well-tolerated in combination with provider/patient choice of endocrine therapy.