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The CDK4/6 Inhibitor Dosing K...

The CDK4/6 Inhibitor Dosing Knowledge (CDK) Study

Last Updated: 2025-12-03

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE3

Total Enrollment

500 participants

Study Classification

INTERVENTIONAL

Study Start Date

2024-10-29

Study Completion Date

2028-09-01

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Metastatic Breast Cancer

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

500 patients will be enrolled, 250 per arm (Arm 1 being indicated dose, Arm 2 being titrated dose).

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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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).

Group Type EXPERIMENTAL

Palbociclib 125mg

Intervention Type DRUG

Arm 1: Indicated dosing for palbociclib (125 mg orally daily on days 1-21 of 28-day cycle)

Ribociclib 600mg

Intervention Type DRUG

Arm 1: Indicated dosing of ribociclib (600 mg orally daily on days 1-21 of 28-day cycle)

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.

Group Type EXPERIMENTAL

Ribociclib

Intervention Type DRUG

Arm 2: 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.

Palbociclib

Intervention Type DRUG

Arm 2: 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.

Interventions

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Palbociclib 125mg

Arm 1: Indicated dosing for palbociclib (125 mg orally daily on days 1-21 of 28-day cycle)

Intervention Type DRUG

Ribociclib 600mg

Arm 1: Indicated dosing of ribociclib (600 mg orally daily on days 1-21 of 28-day cycle)

Intervention Type DRUG

Ribociclib

Intervention Type DRUG

Palbociclib

Intervention Type DRUG

Eligibility Criteria

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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.

Minimum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Julie Gralow, MD

Role: PRINCIPAL_INVESTIGATOR

American Society of Clinical Oncology

Locations

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Ironwood Cancer & Research Centers

Chandler, Arizona, United States

Site Status RECRUITING

Ironwood Cancer & Research Centers

Gilbert, Arizona, United States

Site Status RECRUITING

Ironwood Cancer & Research Centers

Glendale, Arizona, United States

Site Status RECRUITING

Ironwood Cancer & Research Centers

Mesa, Arizona, United States

Site Status RECRUITING

Ironwood Cancer & Research Centers

Mesa, Arizona, United States

Site Status RECRUITING

Ironwood Cancer & Research Centers

Phoenix, Arizona, United States

Site Status RECRUITING

Ironwood Cancer & Research Centers

Scottsdale, Arizona, United States

Site Status RECRUITING

University of Colorado Anschutz Medical Campus

Aurora, Colorado, United States

Site Status RECRUITING

UCHealth Cherry Creek Medical Center

Denver, Colorado, United States

Site Status RECRUITING

UCHealth Highlands Ranch Hospital

Highlands Ranch, Colorado, United States

Site Status RECRUITING

Smilow Cancer Hospital Care Center - Derby

Derby, Connecticut, United States

Site Status RECRUITING

Smilow Cancer Hospital Care Center - Fairfield

Fairfield, Connecticut, United States

Site Status RECRUITING

Smilow Cancer Hospital at Glastonbury

Glastonbury, Connecticut, United States

Site Status RECRUITING

Smilow Cancer Hospital Care Center - Greenwich

Greenwich, Connecticut, United States

Site Status RECRUITING

Smilow Cancer Hospital Care Center - Guilford

Guilford, Connecticut, United States

Site Status RECRUITING

Smilow Cancer Hospital at Saint Francis

Hartford, Connecticut, United States

Site Status RECRUITING

Yale University/Yale Cancer Center

New Haven, Connecticut, United States

Site Status RECRUITING

Smilow Cancer Hospital Care Center - North Haven

North Haven, Connecticut, United States

Site Status RECRUITING

Smilow Cancer Hospital Care Center - Torrington

Torrington, Connecticut, United States

Site Status RECRUITING

Smilow Cancer Hospital Care Center - Trumbull

Trumbull, Connecticut, United States

Site Status RECRUITING

Smilow Cancer Hospital Care Center - Waterbury

Waterbury, Connecticut, United States

Site Status RECRUITING

Smilow Cancer Hospital - Waterford

Waterford, Connecticut, United States

Site Status RECRUITING

Miami Cancer Institute

Miami, Florida, United States

Site Status RECRUITING

Miami Cancer Institute

Plantation, Florida, United States

Site Status RECRUITING

Emory University Winship Cancer Institute

Atlanta, Georgia, United States

Site Status RECRUITING

Lewis Cancer and Research Pavilion

Savannah, Georgia, United States

Site Status RECRUITING

The University of Kansas Cancer Center

Westwood, Kansas, United States

Site Status RECRUITING

The Jackson Laboratory (JAX) - Harold Alfond Center for Cancer Care

Augusta, Maine, United States

Site Status RECRUITING

The Jackson Laboratory (JAX) - Northern Light Cancer Care

Brewer, Maine, United States

Site Status RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Site Status RECRUITING

Dana-Farber Brigham Cancer Center Foxborough

Foxborough, Massachusetts, United States

Site Status RECRUITING

Dana-Farber Cancer Institute Merrimack Valley

Methuen, Massachusetts, United States

Site Status RECRUITING

Dana-Farber Brigham Cancer Center at Milford Regional Medical Center

Milford, Massachusetts, United States

Site Status RECRUITING

Dana-Farber Brigham Cancer Center at South Shore Health

Weymouth, Massachusetts, United States

Site Status RECRUITING

Dana-Farber/New Hampshire Oncology-Hematology

Londonderry, New Hampshire, United States

Site Status RECRUITING

Penn Medicine - Princeton Health

Plainsboro, New Jersey, United States

Site Status RECRUITING

Lovelace Medical Center - Saint Joseph Square

Albuquerque, New Mexico, United States

Site Status RECRUITING

Lovelace Women's Hospital

Albuquerque, New Mexico, United States

Site Status RECRUITING

Presbyterian Kaseman Hospital

Albuquerque, New Mexico, United States

Site Status RECRUITING

The University of New Mexico Comprehensive Cancer Center

Albuquerque, New Mexico, United States

Site Status RECRUITING

Memorial Medical Center

Las Cruces, New Mexico, United States

Site Status RECRUITING

Presbyterian Rust Medical Center/Jorgensen Cancer Center

Rio Rancho, New Mexico, United States

Site Status RECRUITING