The CDK4/6 Inhibitor Dosing Knowledge (CDK) Study

Metastatic Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06377852
• Other study ID #: Pro00075309
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: October 28, 2024
• Est. completion date: September 1, 2028

Study information

• Verified date: April 2024
• Source: American Society of Clinical Oncology
• Contact: Pam Mangat, MS
• Phone: 571-483-1300
• Email: CDKstudy[@]asco.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to generate evidence on an alternative dosing strategy for CDK4/6 inhibitors to help more patients with 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 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 (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).

Description:

The CDK4/6 Inhibitor Dosing Knowledge Study (CDK Study) will study CDK4/6 inhibitor dosing regimens in patients 65 or older with 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 500
• Est. completion date: September 1, 2028
• Est. primary completion date: August 31, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years and older

Eligibility

Inclusion Criteria:

1. Participants must have histologically confirmed 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.

2. Participants must be candidates for initiation of CDK4/6 inhibitor therapy, either palbociclib or ribociclib, in combination with endocrine therapy in the first line setting, in the judgement of the treating provider. The planned endocrine partner can be an aromatase inhibitor (letrozole, anastrozole, exemestane) or fulvestrant, selected through patient/provider choice.

3. People 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 <5 x institutional upper limit of normal (ULN) (participants with documented Gilbert's disease are allowed total bilirubin up to 1.5X ULN)
• AST (SGOT)/ALT (SGPT) <5 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.

6. Participants with known HIV infection without active opportunistic infections are eligible.

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. No prior chemotherapy for metastatic breast cancer.

3. Participants who may have had more than 30 days of endocrine therapy as monotherapy in the first-line metastatic setting prior to entering the study.

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

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

6. Participants who are receiving concurrent therapy with other investigational agents.

7. Patients with stable and/or treated brain metastases are allowed. Patients with rapidly progressive brain metastases are excluded.

8. Patients with 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 listed in Appendix 14 that are known to prolong the QT interval.

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastatic Breast Cancer

Intervention

Drug:
• Palbociclib
Approved dosing for palbociclib (125 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) and escalating the dose if well-tolerated in combination with provider/patient choice of endocrine therapy.
• Ribociclib
Approved dosing of 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 ribociclib (400 mg or 200 mg) and escalating the dose if well-tolerated in combination with provider/patient choice of endocrine therapy.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
American Society of Clinical Oncology	Patient-Centered Outcomes Research Institute

Outcome

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