IMPORTANT Study - IMPORTANT Project

In Brief

IMPORTANT study is a multi-centre, open-label, prospective, randomized-controlled, non-inferiority trial with a pragmatic approach. This study involves both male and female 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: (1) the use of comprehensive geriatric assessment (CGA) approach in treatment decision making; and (2) the use of CDK 4/6-inhibitors as the initial treatment of choice. The purpose is 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.

Study Population

The IMPORTANT study involves older breast cancer patients (≥ 70 years old) with advanced HR-positive/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.

Trial Design

The IMPORTANT study is a phase III & IV Integrated, multi-centre, open-label, prospective, randomized, controlled, non-inferiority trial with a pragmatic approach (Low Intervention Trial)

Aims

The IMPORTANT study aims to investigate the time to treatment failure in vulnerable or frail older breast cancer patients treated with lower initial dose of CDK 4/6-inhibitors plus endocrine therapy compared to the recommended full dose of CDK 4/6-inhibitors.

Additionally, the IMPORTANT trial also aims to compare the two treatment arms (lower initial dose of CDK 4/6-inhibitor vs. full dose) in terms of overall survival, investigator-assessed progression-free survival, time to chemotherapy initiation, treatment tolerability, patients’ quality of life, cost-effectiveness and overall treatment utility, which is a composite endpoint integrating efficacy, tolerability, quality of life as well as patient acceptability.

Research Questions

Question 1

Does a CGA-based initial dose modification scheme for CDK 4/6-inhibitors for vulnerable/frail older patients with advanced breast cancer result in a similar time to treatment failure compared to full dose CDK 4/6-inhibitors?

Question 2

Does lower initial dose of CDK 4/6-inhibitors impact OS, PFS and time to chemotherapy initiation?

Question 3

Does lower initial dose CDK 4/6-inhibitors offer advantages in terms of OTU?

Question 4

Does lower initial dose of CDK 4/6-inhibitors provide advantages in terms of patient-reported outcomes?

Question 5

Does lower initial dose of CDK 4/6-inhibitors provide advantages in terms of cost-effectiveness?

Study Endpoints

The primary endpoint of the IMPORTANT study is time to treatment failure which is the time from randomization to treatment discontinuation because of any reason including disease progression, treatment toxicity, or death due to any cause.

Overall Treatment Utility which is 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.

Overall survival which is the time from randomization to death from any cause.

Progression free survival which is the time from randomization to first documented evidence of disease progression or death from any cause.

Frequency of Adverse Events (Toxicity) which 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.

Time to chemotherapy initiation which is the time from randomization until the initiation of chemotherapy at any treatment line after CDK 4/6-inhibitors.

Time until QoL deterioration which is 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.

Assessment of Quality of Life (QoL) which will be assessed using three validated questionnaires, EORTC QLQ-C30, ELD-14, and EQ-5D-5L.

Cost-effectiveness in which resource use, length of life and quality of life data will be collected during the trial for the purpose of conducting an economic evaluation.

Sample Size

30

Months

The accrual period for the IMPORTANT study is 30 months

495

Patients

This study will include 495 patients

149

For the fit cohort

It aims to recruit 149 patients for the fit cohort

346

For the vulnerable / frail cohort

It also aims to recruit 346 patients for the vulnerable / frail cohort

Follow Up

The IMPORTANT study has two follow-up phases as below

Treatment Phase

Follow-up for efficacy outcome and overall treatment utility take place every three (+/- one) months post randomization. Follow-up for questionnaire assessments take place at 3, 6, 9, 12, 15, 18, 21, and 24 months post randomization depending on the questionnaire. Follow-up for toxicity is before each cycle and up to 28 days after the end of CDK 4/6-inhibitors. This phase continues until disease progression, participant/clinician decision to stop or up to 24 months.

Post-treatment Phase

It will continue after the treatment phase and will collect information until death, lost to follow up, consent withdrawal by the patient, or up to 5 years from treatment initiation for each patient.