Implementing Geriatric Assessment for Dose Optimization of Cyclin-dependent Kinase (CDK) 4/6-inhibitors in Older Breast Cancer Patients

Study Overview
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Brief Summary
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IMPORTANT study is a multicenter, open-label, prospective, randomized-controlled, non-inferiority trial with a pragmatic approach involving older patients (≥ 70 years old) with advanced hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, not amenable for curative treatment and without prior therapy for advanced disease, who are suitable to receive CDK 4/6-inhibitors plus endocrine therapy as first line therapy. The study implements two approaches with high level of evidence, namely the use of comprehensive geriatric assessment (CGA) approach in treatment decision making and the use of CDK 4/6-inhibitors as the initial treatment of choice, to investigate whether a common clinical practice (starting dose reduction of CDK 4/6-inhibitors in older patients) with evidence of low certainty can be standardized using a more individualized-based approach. On the basis of baseline CGA assessment, patients will either receive full dose of CDK 4/6-inhibitors plus endocrine therapy (if patients are fit according to CGA) or be randomized to full dose vs. reduced initial dose of CDK 4/6-inhibitors (if vulnerable or frail according to CGA). The study hypothesis is that adjusting the dose according to vulnerability will allow patients to tolerate treatment better without jeopardizing the treatment efficacy. This project has received funding from the European Union's HORIZON 2022 research and innovation actions supporting the implementation of the Mission on Cancer under grant agreement No 101104589.

Official Title
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Implementing Geriatric Assessment for Dose Optimization of CDK 4/6-inhibitors in Older Breast Cancer Patients - a Pragmatic Randomized-controlled Trial (IMPORTANT Trial)

Conditions
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Metastatic Breast Cancer, Advanced Breast Cancer, Quality of Life, Toxicity, Older Patients

Intervention / Treatment
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* Drug: CDK 4/6 inhibitors
* Drug: Endocrine therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The following inclusion criteria will be applied: Patients male or female aged at least 70 years old at the time of informed consent. Histologically or cytologically confirmed diagnosis of HR-positive (defined as estrogen-receptor ≥ 1%), HER2-negative breast cancer according to analysis of the most recent tumor specimen by local laboratory. Advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative treatment. No prior systemic treatment for advanced disease (recurrence during neo-/adjuvant endocrine therapy is allowed). A prior period of treatment with aromatase inhibitors or fulvestrant for up to 28 days from the CDK 4/6-inhibitor initiation is allowed. Adjuvant treatment with CDK 4/6-inhibitors is allowed provided a disease-free interval from treatment end >12 months. Either measurable disease or non-measurable bone only disease, but evaluable according to RECIST criteria 1.1. Written informed consent prior to any study-specific procedures. Adequate organ function as defined in the summary of product characteristics (SmPC) for the CDK 4/6-inhibitors that is planned to be used. Able to swallow capsules. Able to understand and consent in English language or in native language for each participating country. Exclusion Criteria: Eligible patients will be excluded if they have one of the following criteria: Patients considered from treating physician as non-suitable for treatment with CDK 4/6-inhibitors. Contraindications according to SmPC for the CDK 4/6-inhibitors that is planned to be used. Presence of visceral crisis, lymphangitis carcinomatosis, or leptomeningeal carcinomatosis. History of any other cancer (except of non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission with no therapy for a minimum of 3 years. Participating in other interventional trial.

Ages Eligible for Study
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Minimum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lower initial dose of CDK 4/6-inhibitor (vulnerable/frail patient cohort)<br>-1 level dose reduction as initial dose of either one of the CDK 4/6-inhibitors: Palbociclib 100 mg x 1 for 21 days with 7 days off; or Ribociclib 400 mg x 1 for 21 days with 7 days off; or Abemaciclib 100 mg x 2 daily added to endocrine therapy. | Drug: CDK 4/6 inhibitors<br>* Either Palbociclib, Ribociclib or Abemaciclib<br>Drug: Endocrine therapy<br>* Either Letrozole, Anastrozole, Exemestane or Fulvestrant in combination with CDK 4/6-inhibitor<br>|
| Active Comparator: Full initial dose of CDK 4/6-inhibitor (vulnerable/frail patient cohort)<br>Full initial dose of either one of the CDK 4/6-inhibitors: Palbociclib 125 mg x 1 for 21 days with 7 days off; or Ribociclib 600 mg x 1 for 21 days with 7 days off; or Abemaciclib 150 mg x 2 daily) added to physician's choice endocrine therapy. | Drug: CDK 4/6 inhibitors<br>* Either Palbociclib, Ribociclib or Abemaciclib<br>Drug: Endocrine therapy<br>* Either Letrozole, Anastrozole, Exemestane or Fulvestrant in combination with CDK 4/6-inhibitor<br>|
| Other: Full initial dose of CDK 4/6-inhibitor (fit patient cohort)<br>Full initial dose of either one of the CDK 4/6-inhibitors: Palbociclib 125 mg x 1 for 21 days with 7 days off; or Ribociclib 600 mg x 1 for 21 days with 7 days off; or Abemaciclib 150 mg x 2 daily) added to physician's choice endocrine therapy. | Drug: CDK 4/6 inhibitors<br>* Either Palbociclib, Ribociclib or Abemaciclib<br>Drug: Endocrine therapy<br>* Either Letrozole, Anastrozole, Exemestane or Fulvestrant in combination with CDK 4/6-inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to treatment failure | The time from randomization to treatment discontinuation because of any reason including disease progression, treatment toxicity, or death due to any cause. | Up to 5 years from treatment initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall treatment utility (OTU) | A composite endpoint that will be assessed at the first efficacy evaluation. OTU incorporates objective and participant-reported outcome measures of anticancer efficacy, tolerability and acceptability of treatment providing a simple good, intermediate or poor categorization of outcome. | Three months after treatment initiation | 
| Overall survival | The time from randomization to death from any cause. | Up to 5 years from treatment initiation | 
| Progression free survival | The time from randomization to first documented evidence of disease progression or death from any cause. | Up to 5 years from treatment initiation | 
| Time to chemotherapy initiation | The time from randomization until the initiation of chemotherapy at any treatment line after CDK 4/6-inhibitors. | Up to 5 years from treatment initiation | 
| Frequency of adverse events | Adverse events will be assessed based on adverse events, as graded by CTCAE v 5.0 before each cycle and up to 28 days after the end of CDK 4/6-inhibitors. | Up to 5 years from treatment initiation | 
| Assessment of Quality of life | Quality of life will be assessed using three validated questionnaires, EORTC Quality of Life Questionnaire (QLQ)-C30, Elderly (ELD)-14, and European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L). | Until disease progression, participant / physician decision to stop, death, or up to 24 months from treatment initiation whichever occurs first | 
| Time until Quality of life deterioration | QoL deterioration, defined as the time from randomization until any clinically meaningful worsening (using minimal important differences as cut-off) of any QoL aspect measured by the questionnaires. | Until disease progression, participant / physician decision to stop, death, or up to 24 months from treatment initiation whichever occurs first | 
| Cost effectiveness | Resource use, length of life and quality of life data will be collected during the trial for the purpose of conducting an economic evaluation. | Up to 24 months from treatment initiation |