The CDK4/6 Inhibitor Dosing Knowledge (CDK) Study

The CDK4/6 Inhibitor Dosing Knowledge Study (CDK Study) will study CDK4/6 inhibitor dosing regimens in patients 65 or older with Metastatic Breast Cancer (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. ≥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.

Inclusion criteria

• 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. Verification of histology is preferred at the time of recurrence and where not possible or necessary in the judgment of the treating physician, the study will accept histology from the initial diagnosis.
• Candidate for planned endocrine therapy in combination with 1st use of palbociclib or ribociclib, in the metastatic setting. The planned endocrine partner can be an aromatase inhibitor (letrozole, anastrozole, exemestane) or fulvestrant, selected through patient/provider choice.
• Aged 65 years or older
• Adequate bone marrow and organ function. Laboratory values must be within normal institutional limits, or within ranges as indicated below, or demonstrate minor abnormalities that are deemed clinically non-significant by the investigator.

• Absolute neutrophil count ≥ 1,000/µL
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (participants with documented Gilbert's disease are allowed total bilirubin up to 5X ULN)
• AST (SGOT)/ALT (SGPT) <3 x institutional ULN, or ≤ 5 x ULN for subjects with documented metastatic disease to the liver.
• Baseline QTc ≤ 480 ms (only for ribociclib patients)
• Ability to understand and the willingness to provide informed consent. Note: Remote consent is allowed per institutional guidelines.

Exclusion criteria

• 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.
• Received greater than 30 days (in the metastatic setting) of the specific endocrine therapy agent planned as partner to the CDK4/6 inhibitor in the study at the time of randomization.
• Known history of intolerance or allergy to the planned agents used in this trial.
• Uncontrolled intercurrent illness that, as evaluated by the treating clinician, would hinder compliance with study requirements.
• Concurrent therapy with other investigational agents.
• Rapidly progressive brain metastases.
• 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.
• Current use of drugs that have known potential to prolong the QT interval (e.g., antiarrhythmic drugs), for patients on ribociclib. Note: If concomitant use cannot be avoided, monitor ECG when initiating, during concomitant use, and as clinically indicated. Refer to crediblemeds.org as a resource.
• Prior or concurrent malignancies that are undergoing active treatment.