The CDK4/6 Inhibitor Dosing Knowledge (CDK) Study

May 11, 2026 updated by: American Society of Clinical Oncology

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

500

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Arizona
      • Chandler, Arizona, United States, 85224
        • Recruiting
        • Ironwood Cancer & Research Centers
        • Contact:
        • Principal Investigator:
          • Sumeet Mendonca, MD
      • Gilbert, Arizona, United States, 85297
        • Recruiting
        • Ironwood Cancer & Research Centers
        • Contact:
        • Principal Investigator:
          • Sumeet Mendonca, MD
      • Glendale, Arizona, United States, 85306
        • Recruiting
        • Ironwood Cancer & Research Centers
        • Contact:
        • Principal Investigator:
          • Sumeet Mendonca, MD
      • Goodyear, Arizona, United States, 85395
        • Recruiting
        • Ironwood Cancer & Research Centers
        • Contact:
        • Principal Investigator:
          • Sumeet Mendonca, MD
      • Mesa, Arizona, United States, 85202
        • Recruiting
        • Ironwood Cancer & Research Centers
        • Contact:
        • Principal Investigator:
          • Sumeet Mendonca, MD
      • Mesa, Arizona, United States, 85206
        • Recruiting
        • Ironwood Cancer & Research Centers
        • Contact:
        • Principal Investigator:
          • Sumeet Mendonca, MD
      • Phoenix, Arizona, United States, 85028
        • Recruiting
        • Ironwood Cancer & Research Centers
        • Contact:
        • Principal Investigator:
          • Sumeet Mendonca, MD
      • Scottsdale, Arizona, United States, 85260
        • Recruiting
        • Ironwood Cancer & Research Centers
        • Contact:
        • Principal Investigator:
          • Sumeet Mendonca, MD
    • Colorado
      • Aurora, Colorado, United States, 80045
      • Denver, Colorado, United States, 80206
      • Highlands Ranch, Colorado, United States, 80129
    • Connecticut
      • Derby, Connecticut, United States, 06418
        • Recruiting
        • Smilow Cancer Hospital Care Center - Derby
        • Principal Investigator:
          • Maryam Lustberg, MD
        • Contact:
      • Fairfield, Connecticut, United States, 06824
        • Recruiting
        • Smilow Cancer Hospital Care Center - Fairfield
        • Principal Investigator:
          • Maryam Lustberg, MD
        • Contact:
      • Glastonbury, Connecticut, United States, 06033
        • Recruiting
        • Smilow Cancer Hospital at Glastonbury
        • Principal Investigator:
          • Maryam Lustberg, MD
        • Contact:
      • Greenwich, Connecticut, United States, 06830
        • Recruiting
        • Smilow Cancer Hospital Care Center - Greenwich
        • Principal Investigator:
          • Maryam Lustberg, MD
        • Contact:
      • Guilford, Connecticut, United States, 06437
        • Recruiting
        • Smilow Cancer Hospital Care Center - Guilford
        • Principal Investigator:
          • Maryam Lustberg, MD
        • Contact:
      • Hartford, Connecticut, United States, 06105
        • Recruiting
        • Smilow Cancer Hospital at Saint Francis
        • Principal Investigator:
          • Maryam Lustberg, MD
        • Contact:
      • New Haven, Connecticut, United States, 06510
        • Recruiting
        • Smilow Cancer Hospital - Yale New Haven Health
        • Contact:
        • Principal Investigator:
          • Maryam Lustberg, MD, MPH
      • New Haven, Connecticut, United States, 06510
        • Recruiting
        • Yale University/Yale Cancer Center/Yale School of Medicine
        • Principal Investigator:
          • Maryam Lustberg, MD
        • Contact:
      • North Haven, Connecticut, United States, 06473
        • Recruiting
        • Smilow Cancer Hospital Care Center - North Haven
        • Principal Investigator:
          • Maryam Lustberg, MD
        • Contact:
      • Torrington, Connecticut, United States, 06790
        • Recruiting
        • Smilow Cancer Hospital Care Center - Torrington
        • Principal Investigator:
          • Maryam Lustberg, MD
        • Contact:
      • Trumbull, Connecticut, United States, 06611
        • Recruiting
        • Smilow Cancer Hospital Care Center - Trumbull
        • Principal Investigator:
          • Maryam Lustberg, MD
        • Contact:
      • Waterbury, Connecticut, United States, 06708
        • Recruiting
        • Smilow Cancer Hospital Care Center - Waterbury
        • Principal Investigator:
          • Maryam Lustberg
        • Contact:
      • Waterford, Connecticut, United States, 06385
        • Recruiting
        • Smilow Cancer Hospital - Waterford
        • Principal Investigator:
          • Maryam Lustberg, MD
        • Contact:
    • Florida
      • Miami, Florida, United States, 33176
        • Recruiting
        • Miami Cancer Institute
        • Principal Investigator:
          • Reshma Mahtani, DO
        • Contact:
      • Plantation, Florida, United States, 33324
        • Recruiting
        • Miami Cancer Institute
        • Principal Investigator:
          • Reshma Mahtani, DO
        • Contact:
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Recruiting
        • Emory University Winship Cancer Institute
        • Principal Investigator:
          • Kevin Kalinsky, MD
        • Contact:
      • Savannah, Georgia, United States, 31405
        • Recruiting
        • Lewis Cancer and Research Pavilion
        • Contact:
        • Principal Investigator:
          • Leonard Henry, MD
    • Kansas
      • Westwood, Kansas, United States, 66205
        • Recruiting
        • The University of Kansas Cancer Center
        • Contact:
        • Principal Investigator:
          • Ryan Rader, MD
    • Maine
      • Augusta, Maine, United States, 04330
        • Recruiting
        • The Jackson Laboratory (JAX) - Harold Alfond Center for Cancer Care
        • Contact:
        • Principal Investigator:
          • Erin Adler, DO
      • Brewer, Maine, United States, 04412
        • Recruiting
        • The Jackson Laboratory (JAX) - Northern Light Cancer Care
        • Contact:
        • Principal Investigator:
          • Sarah Sinclair, DO
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Recruiting
        • Dana-Farber Cancer Institute
        • Principal Investigator:
          • Erica Mayer, MD
        • Contact:
          • Call
          • Phone Number: 877-338-7425
      • Foxborough, Massachusetts, United States, 02035
        • Recruiting
        • Dana-Farber Brigham Cancer Center Foxborough
        • Contact:
          • 877-DF-TRIAL
          • Phone Number: 877-338-7425
        • Principal Investigator:
          • Sudha Bolla, MD
      • Methuen, Massachusetts, United States, 01844
        • Recruiting
        • Dana-Farber Cancer Institute Merrimack Valley
        • Contact:
          • 877-DF-TRIAL
          • Phone Number: 877-338-7425
        • Principal Investigator:
          • Ankur Mehta, MD
      • Milford, Massachusetts, United States, 01757
        • Recruiting
        • Dana-Farber Brigham Cancer Center at Milford Regional Medical Center
        • Principal Investigator:
          • Natalie Sinclair, MD
        • Contact:
          • 877-DF-TRIAL
          • Phone Number: 877-338-7425
      • Weymouth, Massachusetts, United States, 02190
        • Recruiting
        • Dana-Farber Brigham Cancer Center at South Shore Health
        • Principal Investigator:
          • James Stoeckle, MD
        • Contact:
          • 877-DF-TRIAL
          • Phone Number: 877-338-7425
    • New Hampshire
      • Londonderry, New Hampshire, United States, 03053
        • Recruiting
        • Dana-Farber/New Hampshire Oncology-Hematology
        • Principal Investigator:
          • Jeanna Walsh, MD
        • Contact:
          • 877-DF-TRIAL
          • Phone Number: 877-338-7425
    • New Jersey
      • Plainsboro, New Jersey, United States, 08536
        • Recruiting
        • Penn Medicine - Princeton Health
        • Principal Investigator:
          • Ramy Sedhom, MD
        • Contact:
    • New Mexico
      • Albuquerque, New Mexico, United States, 87110
        • Recruiting
        • Presbyterian Kaseman Hospital
        • Principal Investigator:
          • Bernard Tawfik, MD
        • Contact:
      • Albuquerque, New Mexico, United States, 87109
        • Recruiting
        • Lovelace Women's Hospital
        • Principal Investigator:
          • Bernard Tawfik, MD
        • Contact:
      • Albuquerque, New Mexico, United States, 87102
        • Recruiting
        • Lovelace Medical Center - Saint Joseph Square
        • Principal Investigator:
          • Bernard Tawfik, MD
        • Contact:
      • Albuquerque, New Mexico, United States, 87131
        • Recruiting
        • The University of New Mexico Comprehensive Cancer Center
        • Principal Investigator:
          • Bernard Tawfik, MD
        • Contact:
      • Las Cruces, New Mexico, United States, 88011
        • Recruiting
        • Memorial Medical Center
        • Principal Investigator:
          • Bernard Tawfik, MD
        • Contact:
      • Rio Rancho, New Mexico, United States, 87124
        • Recruiting
        • Presbyterian Rust Medical Center/Jorgensen Cancer Center
        • Principal Investigator:
          • Bernard Tawfik, MD
        • Contact:
    • North Carolina
      • Albemarle, North Carolina, United States, 28001
        • Recruiting
        • Levine Cancer Institute
        • Principal Investigator:
          • Neelam Desai, MD
        • Contact:
      • Charlotte, North Carolina, United States, 28204
        • Recruiting
        • Levine Cancer Institute
        • Principal Investigator:
          • Neelam Desai, MD
        • Contact:
      • Charlotte, North Carolina, United States, 28210
        • Recruiting
        • Levine Cancer Institute
        • Principal Investigator:
          • Neelam Desai, MD
        • Contact:
      • Charlotte, North Carolina, United States, 28211
        • Recruiting
        • Levine Cancer Institute
        • Principal Investigator:
          • Neelam Desai, MD
        • Contact:
      • Charlotte, North Carolina, United States, 28262
        • Recruiting
        • Levine Cancer Institute
        • Principal Investigator:
          • Neelam Desai, MD
        • Contact:
      • Charlotte, North Carolina, United States, 28277
        • Recruiting
        • Levine Cancer Institute
        • Principal Investigator:
          • Neelam Desai, MD
        • Contact:
      • Concord, North Carolina, United States, 28025
        • Recruiting
        • Levine Cancer Institute
        • Principal Investigator:
          • Neelam Desai, MD
        • Contact:
      • Forest City, North Carolina, United States, 28043
        • Recruiting
        • Levine Cancer Institute
        • Principal Investigator:
          • Neelam Desai, MD
        • Contact:
      • Gastonia, North Carolina, United States, 28054
        • Recruiting
        • Levine Cancer Institute
        • Principal Investigator:
          • Neelam Desai, MD
        • Contact:
      • Huntersville, North Carolina, United States, 28078
        • Recruiting
        • Levine Cancer Institute
        • Principal Investigator:
          • Neelam Desai, MD
        • Contact:
      • Lincolnton, North Carolina, United States, 28092
        • Recruiting
        • Levine Cancer Institute
        • Principal Investigator:
          • Neelam Desai, MD
        • Contact:
      • Matthews, North Carolina, United States, 28104
        • Recruiting
        • Levine Cancer Institute
        • Principal Investigator:
          • Neelam Desai, MD
        • Contact:
      • Monroe, North Carolina, United States, 28112
        • Recruiting
        • Levine Cancer Institute
        • Principal Investigator:
          • Neelam Desai, MD
        • Contact:
      • Shelby, North Carolina, United States, 28150
        • Recruiting
        • Levine Cancer Institute
        • Principal Investigator:
          • Neelam Desai, MD
        • Contact:
    • Pennsylvania
      • Lancaster, Pennsylvania, United States, 17601
        • Recruiting
        • Penn Medicine - Lancaster General Hospital
        • Contact:
        • Principal Investigator:
          • Ramy Sedhom, MD
      • Philadelphia, Pennsylvania, United States, 19104
        • Recruiting
        • Penn Medicine - Perelman Center for Advanced Medicine
        • Principal Investigator:
          • Ramy Sedhom, MD
        • Contact:
      • Philadelphia, Pennsylvania, United States, 19106
        • Recruiting
        • Penn Medicine - Pennsylvania Hospital
        • Contact:
        • Principal Investigator:
          • Ramy Sedhorn, MD
      • West Chester, Pennsylvania, United States, 19380
    • Rhode Island
      • Westerly, Rhode Island, United States, 02891
        • Recruiting
        • Smilow Cancer Hospital - Westerly
        • Principal Investigator:
          • Maryam Lustberg, MD
        • Contact:
    • South Carolina
      • Bluffton, South Carolina, United States, 29910
        • Recruiting
        • St. Joseph's Candler Bluffton Campus
        • Contact:
        • Principal Investigator:
          • Leonard Henry, MD
      • Hilton Head Island, South Carolina, United States, 29926
        • Recruiting
        • SC Cancer Specialists - Hilton Head at St. Joseph's/Candler
        • Contact:
        • Principal Investigator:
          • Leonard Henry, MD
      • Rock Hill, South Carolina, United States, 29732
        • Recruiting
        • Levine Cancer Institute
        • Principal Investigator:
          • Neelam Desai, MD
        • Contact:
    • Tennessee
      • Memphis, Tennessee, United States, 38120
        • Recruiting
        • Baptist Memorial Healthcare
        • Principal Investigator:
          • Glenn Roma, MD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Older Adult

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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).
Drug: Palbociclib 125mg
Arm 1: Indicated dosing for palbociclib (125 mg orally daily on days 1-21 of 28-day cycle)
Drug: Ribociclib 600mg
Arm 1: Indicated dosing of ribociclib (600 mg orally daily on days 1-21 of 28-day cycle)
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.
Drug: Ribociclib
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.
Drug: Palbociclib
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to Treatment Discontinuation (TTD)
Time Frame: up to 48 months
Our primary outcome is time to CDK4/6 inhibitor discontinuation (TTD): the number of days between randomization and the last day the patient takes any dose of the same CDK4/6 inhibitor (regardless of drug holds, dose changes
up to 48 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Toxicity (grade 3-4 AEs)
Time Frame: up to 48 months
Assessed in each arm of the study and study drug
up to 48 months
Event-Free survival (EFS)
Time Frame: up to 48 months
Assessed in each arm of the study and study drug
up to 48 months
Quality of life assessed by patient reported outcomes
Time Frame: up to 48 months
PROMIS-29 (3 domains of 12 questions, physical function, fatigue, participation in social activities), FACT-G Item GP5 (1 question)
up to 48 months
Time to dose reduction and escalation
Time Frame: up to 48 months
For titrated arm. Assessed in each arm of the study and study drug
up to 48 months
Reason for not escalating
Time Frame: up to 48 months
Assessed in each arm of the study and study drug
up to 48 months
Treatment received (missed doses, cumulative dose, etc.)
Time Frame: up to 48 months
Assessed in each arm of the study and study drug
up to 48 months
Healthcare utilization (ED visits, hospital admissions, etc.)
Time Frame: up to 48 months
ED visits, hospital admissions, etc., assessed in each arm of the study and study drug
up to 48 months
Body Mass Index
Time Frame: up to 48 months
weight and height will be combined to report BMI in kg/m^2
up to 48 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

American Society of Clinical Oncology

Collaborators

Patient-Centered Outcomes Research Institute

Investigators

  • Principal Investigator: Julie Gralow, MD, American Society of Clinical Oncology

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 29, 2024

Primary Completion (Estimated)

August 31, 2028

Study Completion (Estimated)

September 1, 2028

Study Registration Dates

First Submitted

April 8, 2024

First Submitted That Met QC Criteria

April 17, 2024

First Posted (Actual)

April 22, 2024

Study Record Updates

Last Update Posted (Actual)

May 13, 2026

Last Update Submitted That Met QC Criteria

May 11, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pro00075309

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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