Clinical trial NCT06377852: The CDK4/6 Inhibitor Dosing Knowledge (CDK) Study
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Metastatic Breast Cancer
Keywords: MBC
Lead sponsor: American Society of Clinical Oncology
Sponsor class: OTHER
Collaborators: name: Patient-Centered Outcomes Research Institute
First posted: 2024-04-22
Enrollment: 500
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 500 patients will be enrolled, 250 per arm (Arm 1 being indicated dose, Arm 2 being titrated dose).
Primary purpose: TREATMENT

Brief 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).

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.

Eligibility criteria: 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.

   * Absolute neutrophil count ≥ 1,000/µL
   * Platelets ≥ 100,000/µL
   * Hemoglobin ≥ 9g/dL
   * 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.
   * Creatinine ≤ institutional ULN or creatinine clearance ≥ 30 mL/min/1.73 m2 for subjects with creatinine levels above institutional ULN.
   * Baseline QTc ≤ 480 ms (only for ribociclib patients)
5. Ability to understand and the willingness to sign a written informed consent document.

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. May have received no more than 30 days of the endocrine therapy agent planned as the partner to the CDK4/6 inhibitor in the study.
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.

9. Current use of drugs known to prolong the QT interval. 10. Prior or concurrent malignancies that are undergoing active treatment.

Primary outcomes:
measure: Time to Treatment Discontinuation (TTD)
timeFrame: up to 48 months
Secondary outcomes:
measure: Toxicity (grade 3-4 AEs)
timeFrame: up to 48 months
measure: Event-Free survival (EFS)
timeFrame: up to 48 months
measure: Quality of life assessed by patient reported outcomes
timeFrame: up to 48 months
measure: Time to dose reduction and escalation
timeFrame: up to 48 months
measure: Reason for not escalating
timeFrame: up to 48 months
measure: Treatment received (missed doses, cumulative dose, etc.)
timeFrame: up to 48 months
measure: Healthcare utilization (ED visits, hospital admissions, etc.)
timeFrame: up to 48 months
measure: Body Mass Index
timeFrame: up to 48 months
Other outcomes:
Locations:
city: Chandler
country: United States
facility: Ironwood Cancer & Research Centers
state: Arizona
city: Gilbert
country: United States
facility: Ironwood Cancer & Research Centers
state: Arizona
city: Glendale
country: United States
facility: Ironwood Cancer & Research Centers
state: Arizona
city: Mesa
country: United States
facility: Ironwood Cancer & Research Centers
state: Arizona
city: Mesa
country: United States
facility: Ironwood Cancer & Research Centers
state: Arizona
city: Phoenix
country: United States
facility: Ironwood Cancer & Research Centers
state: Arizona
city: Scottsdale
country: United States
facility: Ironwood Cancer & Research Centers
state: Arizona
city: Aurora
country: United States
facility: University of Colorado Anschutz Medical Campus
state: Colorado
city: Derby
country: United States
facility: Smilow Cancer Hospital Care Center - Derby
state: Connecticut
city: Fairfield
country: United States
facility: Smilow Cancer Hospital Care Center - Fairfield
state: Connecticut
city: Glastonbury
country: United States
facility: Smilow Cancer Hospital at Glastonbury
state: Connecticut
city: Greenwich
country: United States
facility: Smilow Cancer Hospital Care Center - Greenwich
state: Connecticut
city: Guilford
country: United States
facility: Smilow Cancer Hospital Care Center - Guilford
state: Connecticut
city: Hartford
country: United States
facility: Smilow Cancer Hospital at Saint Francis
state: Connecticut
city: New Haven
country: United States
facility: Yale University/Yale Cancer Center
state: Connecticut
city: North Haven
country: United States
facility: Smilow Cancer Hospital Care Center - North Haven
state: Connecticut
city: Torrington
country: United States
facility: Smilow Cancer Hospital Care Center - Torrington
state: Connecticut
city: Trumbull
country: United States
facility: Smilow Cancer Hospital Care Center - Trumbull
state: Connecticut
city: Waterbury
country: United States
facility: Smilow Cancer Hospital Care Center - Waterbury
state: Connecticut
city: Waterford
country: United States
facility: Smilow Cancer Hospital - Waterford
state: Connecticut
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Plantation
country: United States
facility: Miami Cancer Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University Winship Cancer Institute
state: Georgia
city: Savannah
country: United States
facility: Lewis Cancer and Research Pavilion
state: Georgia
city: Westwood
country: United States
facility: The University of Kansas Cancer Center
state: Kansas
city: Augusta
country: United States
facility: The Jackson Laboratory (JAX) - Harold Alfond Center for Cancer Care
state: Maine
city: Brewer
country: United States
facility: The Jackson Laboratory (JAX) - Northern Light Cancer Care
state: Maine
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Foxboro
country: United States
facility: Dana-Farber Brigham Cancer Center Foxborough
state: Massachusetts
city: Methuen
country: United States
facility: Dana-Farber Cancer Institute Merrimack Valley
state: Massachusetts
city: Milford
country: United States
facility: Dana-Farber Brigham Cancer Center at Milford Regional Medical Center
state: Massachusetts
city: Weymouth
country: United States
facility: Dana-Farber Brigham Cancer Center at South Shore Health
state: Massachusetts
city: Londonderry
country: United States
facility: Dana-Farber/New Hampshire Oncology-Hematology
state: New Hampshire
city: Plainsboro
country: United States
facility: Penn Medicine - Princeton Health
state: New Jersey
city: Albuquerque
country: United States
facility: Lovelace Medical Center - Saint Joseph Square
state: New Mexico
city: Albuquerque
country: United States
facility: Lovelace Women's Hospital
state: New Mexico
city: Albuquerque
country: United States
facility: Presbyterian Kaseman Hospital
state: New Mexico
city: Albuquerque
country: United States
facility: The University of New Mexico Comprehensive Cancer Center
state: New Mexico
city: Las Cruces
country: United States
facility: Memorial Medical Center
state: New Mexico
city: Rio Rancho
country: United States
facility: Presbyterian Rust Medical Center/Jorgensen Cancer Center
state: New Mexico
city: Albemarle
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Concord
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Forest City
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Gastonia
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Huntersville
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Lincolnton
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Matthews
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Monroe
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Shelby
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Lancaster
country: United States
facility: Penn Medicine - Lancaster General Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Penn Medicine - Perelman Center for Advanced Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: Penn Medicine - Pennsylvania Hospital
state: Pennsylvania
city: West Chester
country: United States
facility: Penn Medicine - Chester County Hospital
state: Pennsylvania
city: Westerly
country: United States
facility: Smilow Cancer Hospital - Westerly
state: Rhode Island
city: Bluffton
country: United States
facility: St. Joseph's Candler Bluffton Campus
state: South Carolina
city: Hilton Head Island
country: United States
facility: SC Cancer Specialists - Hilton Head at St. Joseph's/Candler
state: South Carolina
city: Rock Hill
country: United States
facility: Levine Cancer Institute
state: South Carolina
city: Memphis
country: United States
facility: Baptist Memorial Healthcare
state: Tennessee
Study officials:
affiliation: American Society of Clinical Oncology
name: Julie Gralow, MD
role: PRINCIPAL_INVESTIGATOR
References: