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RecruitingInterventionalPhase 3

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

NCT ID: NCT06377852Sponsor: American Society of Clinical OncologyLast updated: 2026-06-05

Summary

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.

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.

Arms & interventions

  • DrugPalbociclib 125mg

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

  • DrugRibociclib 600mg

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

  • DrugRibociclib

    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.

  • DrugPalbociclib

    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.

Outcome measures

Primary

  • Time to Treatment Discontinuation (TTD)

    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

    Time frame: up to 48 months

Secondary

  • Toxicity (grade 3-4 AEs)

    Time frame: up to 48 months

  • Event-Free survival (EFS)

    Time frame: up to 48 months

  • Quality of life assessed by patient reported outcomes

    Time frame: up to 48 months

  • Time to dose reduction and escalation

    Time frame: up to 48 months

  • Reason for not escalating

    Time frame: up to 48 months

  • Treatment received (missed doses, cumulative dose, etc.)

    Time frame: up to 48 months

  • Healthcare utilization (ED visits, hospital admissions, etc.)

    Time frame: up to 48 months

  • Body Mass Index

    Time frame: up to 48 months

Eligibility criteria

Sex: AllAge: 65 Years and olderHealthy volunteers: No
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 locations (73)

Ironwood Cancer & Research Centers

Chandler, Arizona, 85224

Recruiting
Berenice Valdez · Contact
480-890-7705berenice.mendez@ironwoodcrc.com
Sumeet Mendonca, MD · Principal Investigator

Ironwood Cancer & Research Centers

Gilbert, Arizona, 85297

Recruiting
Berenice Valdez · Contact
480-890-7705berenice.mendez@ironwoodcrc.com
Sumeet Mendonca, MD · Principal Investigator

Ironwood Cancer & Research Centers

Glendale, Arizona, 85306

Recruiting
Berenice Valdez · Contact
480-890-7705berenice.mendez@ironwoodcrc.com
Sumeet Mendonca, MD · Principal Investigator

Ironwood Cancer & Research Centers

Goodyear, Arizona, 85395

Recruiting
Berenice Valdez · Contact
480-890-7705berenice.mendez@ironwoodcrc.com
Sumeet Mendonca, MD · Principal Investigator

Ironwood Cancer & Research Centers

Mesa, Arizona, 85202

Recruiting
Berenice Valdez · Contact
480-890-7705berenice.mendez@ironwoodcrc.com
Sumeet Mendonca, MD · Principal Investigator

Ironwood Cancer & Research Centers

Mesa, Arizona, 85206

Recruiting
Berenice Valdez · Contact
480-890-7705berenice.mendez@ironwoodcrc.com
Sumeet Mendonca, MD · Principal Investigator

Ironwood Cancer & Research Centers

Phoenix, Arizona, 85028

Recruiting
Berenice Valdez · Contact
480-890-7705berenice.mendez@ironwoodcrc.com
Sumeet Mendonca, MD · Principal Investigator

Ironwood Cancer & Research Centers

Scottsdale, Arizona, 85260

Recruiting
Berenice Valdez · Contact
480-890-7705berenice.mendez@ironwoodcrc.com
Sumeet Mendonca, MD · Principal Investigator

University of Colorado Anschutz Medical Campus

Aurora, Colorado, 80045

Recruiting
Anna Lampart · Contact
303-724-6231anna.lamport@cuanschutz.edu
Enrique Soto, MD · Contact
303-724-6231enrique.2.soto@cuanschutz.edu
Enrique Soto, MD · Principal Investigator

UCHealth Cherry Creek Medical Center

Denver, Colorado, 80206

Recruiting
Anna Lamport · Contact
303-724-6231anna.lamport@cuanschutz.edu
Enrique Soto, MD · Contact
enrique.2.soto@cuanschutz.edu
Enrique Soto, MD · Principal Investigator

UCHealth Highlands Ranch Hospital

Highlands Ranch, Colorado, 80129

Recruiting
Anna Lamport · Contact
303-724-6231anna.lamport@cuanschutz.edu
Enrique Soto, MD · Contact
enrique.2.soto@cuanschutz.edu
Enrique Soto, MD · Principal Investigator

Smilow Cancer Hospital Care Center - Derby

Derby, Connecticut, 06418

Recruiting
Carl Brown · Contact
475-241-1065carl.brown@yale.edu
Maryam Lustberg, MD · Principal Investigator

Smilow Cancer Hospital Care Center - Fairfield

Fairfield, Connecticut, 06824

Recruiting
Carl Brown · Contact
475-241-1065carl.brown@yale.edu
Maryam Lustberg, MD · Principal Investigator

Smilow Cancer Hospital at Glastonbury

Glastonbury, Connecticut, 06033

Recruiting
Carl Brown · Contact
475-241-1065carl.brown@yale.edu
Maryam Lustberg, MD · Principal Investigator

Smilow Cancer Hospital Care Center - Greenwich

Greenwich, Connecticut, 06830

Recruiting
Carl Brown · Contact
475-241-1065carl.brown@yale.edu
Maryam Lustberg, MD · Principal Investigator

Smilow Cancer Hospital Care Center - Guilford

Guilford, Connecticut, 06437

Recruiting
Carl Brown · Contact
475-241-1065carl.brown@yale.edu
Maryam Lustberg, MD · Principal Investigator

Smilow Cancer Hospital at Saint Francis

Hartford, Connecticut, 06105

Recruiting
Carl Brown · Contact
475-241-1065carl.brown@yale.edu
Maryam Lustberg, MD · Principal Investigator

Smilow Cancer Hospital - Yale New Haven Health

New Haven, Connecticut, 06510

Recruiting
Carl Brown · Contact
475-241-1065carl.brown@yale.edu
Maryam Lustberg, MD, MPH · Principal Investigator

Yale University/Yale Cancer Center/Yale School of Medicine

New Haven, Connecticut, 06510

Recruiting
Carl Brown · Contact
475-241-1065carl.brown@yale.edu
Maryam Lustberg, MD · Principal Investigator

Smilow Cancer Hospital Care Center - North Haven

North Haven, Connecticut, 06473

Recruiting
Carl Brown · Contact
475-241-1065carl.brown@yale.edu
Maryam Lustberg, MD · Principal Investigator

Smilow Cancer Hospital Care Center - Torrington

Torrington, Connecticut, 06790

Recruiting
Carl Brown · Contact
475-241-1065carl.brown@yale.edu
Maryam Lustberg, MD · Principal Investigator

Smilow Cancer Hospital Care Center - Trumbull

Trumbull, Connecticut, 06611

Recruiting
Carl Brown · Contact
475-241-1065carl.brown@yale.edu
Maryam Lustberg, MD · Principal Investigator

Smilow Cancer Hospital Care Center - Waterbury

Waterbury, Connecticut, 06708

Recruiting
Carl Brown · Contact
475-241-1065carl.brown@yale.edu
Maryam Lustberg · Principal Investigator

Smilow Cancer Hospital - Waterford

Waterford, Connecticut, 06385

Recruiting
Carl Brown · Contact
475-241-1065carl.brown@yale.edu
Maryam Lustberg, MD · Principal Investigator

Miami Cancer Institute

Miami, Florida, 33176

Recruiting
Kristianne Enriquez · Contact
786-527-8537kristianne.enriquez@baptisthealth.net
Reshma Mahtani, DO · Principal Investigator

Miami Cancer Institute

Plantation, Florida, 33324

Recruiting
Krystal Fernandez · Contact
954-837-1566Krystal.Fernandez@baptisthealth.net
Reshma Mahtani, DO · Principal Investigator

Emory University Winship Cancer Institute

Atlanta, Georgia, 30322

Recruiting
Kevin Kalinsky, MD · Contact
404-778-1868kevin.michael.kalinsky@emory.edu
Kevin Kalinsky, MD · Principal Investigator

Lewis Cancer and Research Pavilion

Savannah, Georgia, 31405

Recruiting
Stephanie Reyes · Contact
912-819-5723smiths1@sjchs.org
Leonard Henry, MD · Principal Investigator

The University of Kansas Cancer Center

Westwood, Kansas, 66205

Recruiting
call or email to be connected · Contact
913-945-7552CTNurseNav@kumc.edu
Ryan Rader, MD · Principal Investigator

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

Augusta, Maine, 04330

Recruiting
Sandra Neptune · Contact
207-626-4811Sandra.Neptune@mainegeneral.org
Erin Adler, DO · Principal Investigator

The Jackson Laboratory (JAX) - Northern Light Cancer Care

Brewer, Maine, 04412

Recruiting
Laurie Lewis · Contact
207-973-4249llewis@northernlight.org
Sarah Sinclair, DO · Principal Investigator

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215

Recruiting
Call · Contact
877-338-7425
Erica Mayer, MD · Principal Investigator

Dana-Farber Brigham Cancer Center Foxborough

Foxborough, Massachusetts, 02035

Recruiting
877-DF-TRIAL · Contact
877-338-7425
Sudha Bolla, MD · Principal Investigator

Dana-Farber Cancer Institute Merrimack Valley

Methuen, Massachusetts, 01844

Recruiting
877-DF-TRIAL · Contact
877-338-7425
Ankur Mehta, MD · Principal Investigator

Dana-Farber Brigham Cancer Center at Milford Regional Medical Center

Milford, Massachusetts, 01757

Recruiting
877-DF-TRIAL · Contact
877-338-7425
Natalie Sinclair, MD · Principal Investigator

Dana-Farber Brigham Cancer Center at South Shore Health

Weymouth, Massachusetts, 02190

Recruiting
877-DF-TRIAL · Contact
877-338-7425
James Stoeckle, MD · Principal Investigator

Dana-Farber/New Hampshire Oncology-Hematology

Londonderry, New Hampshire, 03053

Recruiting
877-DF-TRIAL · Contact
877-338-7425
Jeanna Walsh, MD · Principal Investigator

Penn Medicine - Princeton Health

Plainsboro, New Jersey, 08536

Recruiting
Syed (Momin) Ali · Contact
201-660-5260syed.ali@pennmedicine.upenn.edu
Ramy Sedhom, MD · Principal Investigator

Lovelace Medical Center - Saint Joseph Square

Albuquerque, New Mexico, 87102

Recruiting
Zemmie Pollock · Contact
505-727-3040ZPollock@salud.unm.edu
Bernard Tawfik, MD · Principal Investigator

Lovelace Women's Hospital

Albuquerque, New Mexico, 87109

Recruiting
Zemmie Pollock · Contact
505-727-3040ZPollock@salud.unm.edu
Bernard Tawfik, MD · Principal Investigator

Presbyterian Kaseman Hospital

Albuquerque, New Mexico, 87110

Recruiting
Monique Robertson · Contact
505-559-6100mrobertso2@phs.org
Bernard Tawfik, MD · Principal Investigator

The University of New Mexico Comprehensive Cancer Center

Albuquerque, New Mexico, 87131

Recruiting
Crystal Pichette · Contact
505-925-0380cpichette@salud.unm.edu
Bernard Tawfik, MD · Principal Investigator

Memorial Medical Center

Las Cruces, New Mexico, 88011

Recruiting
Deborah Brown · Contact
575-521-1554Deborah.Brown@LPNT.net
Bernard Tawfik, MD · Principal Investigator

Presbyterian Rust Medical Center/Jorgensen Cancer Center

Rio Rancho, New Mexico, 87124

Recruiting
Andrea Yost · Contact
505-559-6100ayost3@phs.org
Bernard Tawfik, MD · Principal Investigator

Levine Cancer Institute

Albemarle, North Carolina, 28001

Recruiting
Amanda Seifts · Contact
980-442-2391amanda.seifts@advocatehealth.org
Neelam Desai, MD · Principal Investigator

Levine Cancer Institute

Charlotte, North Carolina, 28204

Recruiting
Amanda Seifts · Contact
980-442-2391amanda.seifts@advocatehealth.org
Neelam Desai, MD · Principal Investigator

Levine Cancer Institute

Charlotte, North Carolina, 28210

Recruiting
Amanda Seifts · Contact
980-442-2391amanda.seifts@advocatehealth.org
Neelam Desai, MD · Principal Investigator

Levine Cancer Institute

Charlotte, North Carolina, 28211

Recruiting
Amanda Seifts · Contact
980-442-2391amanda.seifts@advocatehealth.org
Neelam Desai, MD · Principal Investigator

Levine Cancer Institute

Charlotte, North Carolina, 28262

Recruiting
Amanda Seifts · Contact
980-442-2391amanda.seifts@advocatehealth.org
Neelam Desai, MD · Principal Investigator

Levine Cancer Institute

Charlotte, North Carolina, 28277

Recruiting
Amanda Seifts · Contact
980-442-2391amanda.seifts@advocatehealth.org
Neelam Desai, MD · Principal Investigator

Levine Cancer Institute

Concord, North Carolina, 28025

Recruiting
Amanda Seifts · Contact
980-442-2391amanda.seifts@advocatehealth.org
Neelam Desai, MD · Principal Investigator

Levine Cancer Institute

Forest City, North Carolina, 28043

Recruiting
Amanda Seifts · Contact
980-442-2391amanda.seifts@advocatehealth.org
Neelam Desai, MD · Principal Investigator

Levine Cancer Institute

Gastonia, North Carolina, 28054

Recruiting
Amanda Seifts · Contact
980-442-2391amanda.seifts@advocatehealth.org
Neelam Desai, MD · Principal Investigator

Levine Cancer Institute

Huntersville, North Carolina, 28078

Recruiting
Amanda Seifts · Contact
980-442-2391amanda.seifts@advocatehealth.org
Neelam Desai, MD · Principal Investigator

Levine Cancer Institute

Lincolnton, North Carolina, 28092

Recruiting
Amanda Seifts · Contact
980-442-2391amanda.seifts@advocatehealth.org
Neelam Desai, MD · Principal Investigator

Levine Cancer Institute

Matthews, North Carolina, 28104

Recruiting
Amanda Seifts · Contact
980-442-2391amanda.seifts@advocatehealth.org
Neelam Desai, MD · Principal Investigator

Levine Cancer Institute

Monroe, North Carolina, 28112

Recruiting
Amanda Seifts · Contact
980-442-2391amanda.seifts@advocatehealth.org
Neelam Desai, MD · Principal Investigator

Levine Cancer Institute

Shelby, North Carolina, 28150

Recruiting
Amanda Seifts · Contact
980-442-2391amanda.seifts@advocatehealth.org
Neelam Desai, MD · Principal Investigator

Penn Medicine - Lancaster General Hospital

Lancaster, Pennsylvania, 17601

Recruiting
Susan Tollett · Contact
717-544-0511susan.tollett@pennmedicine.upenn.edu
Ramy Sedhom, MD · Principal Investigator

Penn Medicine - Perelman Center for Advanced Medicine

Philadelphia, Pennsylvania, 19104

Recruiting
Erin Freitas · Contact
215-445-7277erin.freitas@pennmedicine.upenn.edu
Ramy Sedhom, MD · Principal Investigator

Penn Medicine - Pennsylvania Hospital

Philadelphia, Pennsylvania, 19106

Recruiting
Clinical Research Team (RNs & CRCs) · Contact
PAhemoncResearch@uphs.upenn.edu
Ramy Sedhorn, MD · Principal Investigator

Penn Medicine - Chester County Hospital

West Chester, Pennsylvania, 19380

Recruiting
Caroline Depiano · Contact
610-738-2522caroline.depiano@pennmedicine.upenn.edu
Ramy Sedhom, MD · Principal Investigator

Smilow Cancer Hospital - Westerly

Westerly, Rhode Island, 02891

Recruiting
Carl Brown · Contact
475-241-1065carl.brown@yale.edu
Maryam Lustberg, MD · Principal Investigator

St. Joseph's Candler Bluffton Campus

Bluffton, South Carolina, 29910

Recruiting
Stephanie Reyes · Contact
912-819-5723smiths1@sjchs.org
Leonard Henry, MD · Principal Investigator

SC Cancer Specialists - Hilton Head at St. Joseph's/Candler

Hilton Head Island, South Carolina, 29926

Recruiting
Stephanie Reyes · Contact
912-819-5723smiths1@sjchs.org
Leonard Henry, MD · Principal Investigator

Levine Cancer Institute

Rock Hill, South Carolina, 29732

Recruiting
Amanda Seifts · Contact
980-442-2391amanda.seifts@advocatehealth.org
Neelam Desai, MD · Principal Investigator

Baptist Memorial Healthcare

Memphis, Tennessee, 38120

Recruiting
Amber Stone · Contact
901-226-1577Amber.Stone@bmhcc.org
Glenn Roma, MD · Principal Investigator

Northwest Medical Specialties

Bonney Lake, Washington, 98391

Recruiting
Jodi Thiel · Contact
253-720-8143jthiel@southsoundcare.org
Frank Senecal, MD · Principal Investigator

Northwest Medical Specialties

Federal Way, Washington, 98003

Recruiting
Jodi Thiel · Contact
253-720-8143jthiel@southsoundcare.org
Frank Senecal, MD · Principal Investigator

Northwest Medical Specialties

Gig Harbor, Washington, 98332

Recruiting
Jodi Thiel · Contact
253-720-8143jthiel@southsoundcare.org
Frank Senecal, MD · Principal Investigator

Northwest Medical Specialties

Olympia, Washington, 98502

Recruiting
Jodi Thiel · Contact
253-720-8143jthiel@southsoundcare.org
Frank Senecal, MD · Principal Investigator

Northwest Medical Specialties

Puyallup, Washington, 98373

Recruiting
Jodi Thiel · Contact
253-720-8143jthiel@southsoundcare.org
Frank Senecal, MD · Principal Investigator

Northwest Medical Specialties

Tacoma, Washington, 98405

Recruiting
Jodi Thiel · Contact
253-720-8143jthiel@southsoundcare.org
Frank Senecal, MD · Principal Investigator