Dalpiciclib With Endocrine Therapy for Advanced Breast Cancer After CDK4/6 Inhibitor Failure (DAWNA-FES)

Study Overview
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Brief Summary
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CDK4/6 inhibitors are currently the standard treatment for female breast cancer patients with HR+ tumors. However, there is no established standard treatment for patients who experience treatment failure with CDK4/6 inhibitors. The MAINTAIN study has shown clinical benefits by switching to Ribociclib and changing endocrine therapy after progression on CDK4/6 inhibitors. We hypothesize that combining Dalpiciclib with physician-selected endocrine therapy, following treatment failure with CDK4/6 inhibitors, would similarly lead to improved patient survival. In this study, 18F-FES PET/CT will be employed as a non-invasive alternative to biopsy techniques for evaluating the expression of ER in various systemic lesions of the patients.

Detailed Description
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With the emergence of targeted therapies, the treatment landscape for patients with hormone receptor-positive (HR+) and HER2-negative (HER2-) metastatic breast cancer (MBC) is continuously evolving. The combination of cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) with endocrine therapy has become the standard treatment approach for first-line therapy or treatment after progression on endocrine therapy. Multiple large randomized studies have demonstrated that the combination of CDK4/6i and endocrine therapy significantly improves progression-free survival (PFS) in HR+/HER2- MBC patients. Updated analyses have also shown a significant improvement in overall survival (OS) with the combination of endocrine therapy and either Palbociclib or Ribociclib. Currently, regulatory agencies have approved four CDK4/6 inhibitors, namely Palbociclib, Abemaciclib, Ribociclib, and Dalpiciclib, for the treatment of HR+/HER2- breast cancer. All four CDK4/6 inhibitors are approved for use in combination with endocrine therapy for advanced HR+/HER2- breast cancer. Abemaciclib has also been approved for use as adjuvant therapy in early-stage breast cancer with HR+/HER2- subtype and high-risk recurrent factors, as well as for the treatment of advanced breast cancer. CDK4/6 inhibitors are currently the standard treatment for female breast cancer patients with HR+ tumors. However, there is no established standard treatment for patients who experience treatment failure with CDK4/6 inhibitors. Despite the extensive clinical experience with these drugs, our understanding of the long-term effects of CDK4/6 blockade in patients previously treated with CDK4/6 inhibitors is limited. The MAINTAIN study has shown clinical benefits by switching to Ribociclib and changing endocrine therapy after progression on CDK4/6 inhibitors. We hypothesize that combining Dalpiciclib with physician-selected endocrine therapy, following treatment failure with CDK4/6 inhibitors, would similarly lead to improved patient survival. 18F-fluorodeoxyglucose (FDG) PET imaging is widely utilized in the field of oncology to detect increased glucose metabolism activity. In the case of breast cancer, 18F-FDG PET/CT imaging is predominantly recommended for patients with unclear staging, advanced disease, or metastasis, when conventional imaging methods are inconclusive. On the other hand, 18F-fluoroestradiol (FES) is an endogenous estrogen analogue that specifically binds to estrogen receptors (ERs). Through PET imaging, FES enables dynamic, quantitative, and non-invasive assessment of ER expression levels and distribution within the patient's body. When combined with 18F-FDG PET or other imaging modalities, 18F-FES PET imaging can evaluate the heterogeneity of ER expression and has the potential to identify ER loss or dysfunction. It has been observed that 18F-FES PET exhibits good correlation with traditional immunohistochemistry for assessing ER expression. Moreover, published human studies have not reported any toxicity or adverse reactions associated with 18F-FES usage. In this study, 18F-FES PET/CT will be employed as a non-invasive alternative to biopsy techniques for evaluating the expression of ER in various systemic lesions of the patients.

Official Title
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An Exploratory Study on Predicting the Efficacy of Dalpiciclib in Combination With Endocrine Therapy for HR-Positive and HER2-Negative Recurrent/Metastatic Breast Cancer Patients After CDK4/6 Inhibitor Treatment Failure Using 18F-FES PET/CT

Conditions
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Advanced Breast Cancer

Intervention / Treatment
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* Drug: The combination of Dalpiciclib with physician-selected endocrine therapy
* Drug: Chemotherapy selected by the physician


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The recent pathology results showed HR-positive and HER2-negative. 18F-FES-PET/CT showed at least one ER-positive lesion. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score: 0-2 points. Expected survival time ≥ 3 months. Previous antitumor therapy: (1) (neo)adjuvant treatment with Palbociclib or Abemaciclib or Ribociclib or relapse after adjuvant treatment with Palbociclib or Abemaciclib or Ribociclib; (2) receiving Palbociclib or Abemaciclib or Ribociclib-based treatment in the context of metastatic breast cancer or disease progression after treatment; (3) previously received ≤1 line of chemotherapy for recurrent or metastatic breast cancer; (4) previously received ≤3 lines of endocrine therapy for recurrent or metastatic breast cancer. Willing to undergo 18F-FDG PET/CT standard imaging. At least one measurable lesion outside the skull according to RECIST V1.1. The function of important organs meets the requirements. The subjects have recovered from any adverse event related to previous tumor treatment (≤ Grade 1) before the first administration of the investigational drug. Exclusion Criteria: 18F-FES-PET/CT shows that all lesions are ER-negative. Previously received treatment with Dalpiciclib. MRI or lumbar puncture confirms leptomeningeal metastasis. Imaging confirms central nervous system metastasis. Participants with visceral crisis, rapid disease progression, and patients not suitable for endocrine therapy. Participants with ascites, baseline pleural effusion with clinical symptoms, and pericardial effusion requiring drainage within the first 4 weeks of treatment. Unable to swallow, intestinal obstruction, or other factors that affect drug administration and absorption. Participants diagnosed with any other malignancy within the past 5 years, excluding non-melanoma skin cancer treated with curative intent. Basal cell or squamous cell skin cancer, or cervical intraepithelial neoplasia and papillary thyroid cancer. Participants who have undergone major surgery or suffered a major injury within 4 weeks before starting treatment, or are expected to undergo major surgical treatment. Known history of allergy to the components of this treatment regimen.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Arm A<br>The combination of Dalpiciclib with physician-selected endocrine therapy | Drug: The combination of Dalpiciclib with physician-selected endocrine therapy<br>* Dalpiciclib: 150 mg, orally, once daily, on days 1-21, every 28 days (3 weeks on, 1 week off) Letrozole: 2.5 mg, orally, once daily (continuous), every 28 days OR Anastrozole: 1.0 mg, orally, once daily (continuous), every 28 days OR Exemestane: 25 mg, orally, once daily (continuous), every 28 days OR Fulvestrant: 500 mg, intramuscular injection on day 1/15 of the first cycle, then on day 1 of each subsequent cycle, every 28 days OR Tamoxifen: 10-20 mg, orally, twice daily (continuous), every 28 days Pre/perimenopausal women also require ovarian function suppression (OFS), which can be achieved through bilateral oophorectomy or the use of gonadotropin-releasing hormone (GnRH) analog drugs<br>|
| Active Comparator: Arm B<br>Chemotherapy selected by the physician | Drug: Chemotherapy selected by the physician<br>* The chemotherapy regimen is chosen by the clinical physician and may include, but is not limited to, the following options: the combination of paclitaxel and capecitabine, the combination of paclitaxel and carboplatin, single-agent capecitabine, single-agent platinum drugs, and the combination of gemcitabine and platinum-based chemotherapy. Each treatment cycle consists of a 21-day duration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator-assessed PFS | The time from the initiation of treatment to the first radiographic assessment of disease progression (PD) or any event leading to death | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Objective Response Rate | Up to approximately 24 months | 
| Disease Control Rate (DCR) | Disease Control Rate | Up to approximately 24 months | 
| Overall Survival (OS) | Overall Survival | Up to approximately 24 months |