Comparing Oral Drug Dosing Strategies in Older Patients with Metastatic Breast Cancer to Maximize Tolerance and Reduce Discontinuation: The CDK4/6 Inhibitor Dosing Knowledge (CDK) Study

The purpose of this study is to generate evidence on an alternative dosing strategy for
CDK4/6 inhibitors to help more patients with Metastatic Breast Cancer (MBC) (age ≥ 65
years) tolerate side effects and stay on treatment longer, to derive the most clinical
benefit from these drugs.

The primary objective of the CDK Study is to compare time to treatment discontinuation
(TTD) on the approved dosing for palbociclib (125 mg orally daily on days 1-21 of 28-day
cycle) or 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
palbociclib (100 mg or 75 mg) or ribociclib (400 mg or 200 mg) and escalating the dose if
well-tolerated in combination with provider/patient choice endocrine therapy (aromatase
inhibitor (AI) or fulvestrant) in patients age 65 or older with HR+/HER2- MBC. The
secondary and exploratory objectives will generate evidence needed to personalize
treatment decisions by comparing patient-centric secondary outcomes and evaluating
baseline factors.

Together with their treating physician, participants will choose the CDK4/6 inhibitor
(palbociclib or ribociclib) and which endocrine therapy (aromatase inhibitor or
fulvestrant) of their choice but will be randomized to either Arm 1 (indicated dosing) or
Arm 2 (titrated dosing).

Note: Telehealth visits are allowed at any time per institutional guidelines. In
addition, the study allows for remote consenting per institutional guidelines.

Inclusion Criteria:

1. 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.

2. 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.

3. Aged 65 years or older

4. 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.

5. Baseline QTc ≤ 480 ms (only for ribociclib patients)

6. Ability to understand and the willingness to provide informed consent. Note: Remote
consent is allowed per institutional guidelines.

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. 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.

3. Known history of intolerance or allergy to the planned agents used in this trial.

4. Uncontrolled intercurrent illness that, as evaluated by the treating clinician,
would hinder compliance with study requirements.

5. Concurrent therapy with other investigational agents.

6. Rapidly progressive brain metastases.

7. 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.

8. 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.

9. Prior or concurrent malignancies that are undergoing active treatment.